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Han X, Zhang Y, Petrosky JN, Bald S, Sherva RM, Labadorf A, Cherry JD, Chung J, Farrell K, Abdolmohammadi B, Durape S, Martin BM, Palmisano JN, Farrell JJ, Alvarez VE, Huber BR, Dwyer B, Daneshvar DH, Dams-O'Connor K, Jun GR, Lunetta KL, Goldstein LE, Katz DI, Cantu RC, Shenton ME, Cummings JL, Reiman EM, Stern RA, Alosco ML, Tripodis Y, Farrer LA, Stein TD, Crary JF, McKee AC, Mez J. A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes. Cell Rep Med 2025; 6:102084. [PMID: 40239644 DOI: 10.1016/j.xcrm.2025.102084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 01/02/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025]
Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. Genetic variation in the 17q21.31 region, containing microtubule-associated protein tau (MAPT), has been implicated in tauopathies but has not been investigated in CTE. The region includes a megabase-long inversion (H1/H2) and copy-number variations, including α, β, and γ segments, which can be characterized as nine segregating structural haplotypes. We leveraged array SNP data and a reference panel across the 17q21.31 region to impute structural haplotypes and test their association with CTE endophenotypes in 447 European ancestry brain donors with RHI exposure. The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE. H1β1γ1 differential expression analyses in dorsolateral frontal cortex implicated cis-acting genes and inflammatory pathways. Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure.
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Affiliation(s)
- Xudong Han
- Bioinformatics Graduate Program, Boston University, Boston, MA, USA; Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Yichi Zhang
- Bioinformatics Graduate Program, Boston University, Boston, MA, USA
| | | | - Sarah Bald
- Bioinformatics Graduate Program, Boston University, Boston, MA, USA
| | - Richard M Sherva
- Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Adam Labadorf
- Bioinformatics Graduate Program, Boston University, Boston, MA, USA; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA
| | - Jonathan D Cherry
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Jaeyoon Chung
- Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Kurt Farrell
- Departments of Pathology, Neuroscience, and Artificial Intelligence & Human Health, Neuropathology Brain Bank & Research CoRE, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bobak Abdolmohammadi
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA
| | - Shruti Durape
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA
| | - Brett M Martin
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA
| | - Joseph N Palmisano
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA
| | - John J Farrell
- Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Victor E Alvarez
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA
| | - Bertrand R Huber
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA
| | - Brigid Dwyer
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Braintree Rehabilitation Hospital, Braintree, MA, USA
| | - Daniel H Daneshvar
- Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA
| | - Kristen Dams-O'Connor
- Department of Rehabilitation and Human Performance, Brain Injury Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gyungah R Jun
- Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Kathryn L Lunetta
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Lee E Goldstein
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Departments of Biomedical, Electrical & Computer Engineering, Boston University College of Engineering, Boston, MA, USA; Departments of Radiology and Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Douglas I Katz
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Braintree Rehabilitation Hospital, Braintree, MA, USA
| | - Robert C Cantu
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Neurosurgery, Emerson Hospital, Concord, MA, USA
| | - Martha E Shenton
- Boston VA Healthcare System, Boston, MA, USA; Psychiatry Neuroimaging Laboratory, Departments of Psychiatry and Radiology, Brigham and Women's Hospital, Boston, MA, USA
| | - Jeffrey L Cummings
- Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - Eric M Reiman
- Banner Alzheimer's Institute, University of Arizona, Arizona State University, Translational Genomics Research Institute, and Arizona Alzheimer's Consortium, Phoenix, AZ, USA
| | - Robert A Stern
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA
| | - Michael L Alosco
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA
| | - Yorghos Tripodis
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Lindsay A Farrer
- Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Thor D Stein
- Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA
| | - John F Crary
- Departments of Pathology, Neuroscience, and Artificial Intelligence & Human Health, Neuropathology Brain Bank & Research CoRE, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ann C McKee
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston VA Healthcare System, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Bedford VA Healthcare System, Bedford, MA, USA
| | - Jesse Mez
- Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Boston University Chronic Traumatic Encephalopathy Center, Boston University, Boston, MA, USA.
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Vialle RA, de Paiva Lopes K, Li Y, Ng B, Schneider JA, Buchman AS, Wang Y, Farfel JM, Barnes LL, Wingo AP, Wingo TS, Seyfried NT, De Jager PL, Gaiteri C, Tasaki S, Bennett DA. Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits. Genome Med 2025; 17:20. [PMID: 40038788 PMCID: PMC11881306 DOI: 10.1186/s13073-025-01444-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 02/24/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci. METHODS By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's disease and other common age-related clinical and neuropathologic traits were examined. RESULTS First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10-4). CONCLUSIONS While still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.
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Affiliation(s)
- Ricardo A Vialle
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA.
| | - Katia de Paiva Lopes
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Yan Li
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Bernard Ng
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Julie A Schneider
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Aron S Buchman
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Yanling Wang
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Jose M Farfel
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Lisa L Barnes
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - Aliza P Wingo
- Department of Psychiatry, University of California, Davis, Davis, CA, USA
- VA Northern California Health Care System, Davis, CA, USA
| | - Thomas S Wingo
- Department of Neurology, University of California, Davis, Davis, CA, USA
| | - Nicholas T Seyfried
- Department of Neurology and Department of Biochemistry, Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Philip L De Jager
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Chris Gaiteri
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Shinya Tasaki
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison St, Chicago, IL, 60612, USA
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Ma Y, Erb ML, Moore DJ. Aging, cellular senescence and Parkinson's disease. JOURNAL OF PARKINSON'S DISEASE 2025; 15:239-254. [PMID: 39973488 DOI: 10.1177/1877718x251316552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1-2% of people over age 65. The risk of developing PD dramatically increases with advanced age, indicating that aging is likely a driving factor in PD neuropathogenesis. Several age-associated biological changes are also hallmarks of PD neuropathology, including mitochondrial dysfunction, oxidative stress, and neuroinflammation. Accumulation of senescent cells is an important feature of aging that contributes to age-related diseases. How age-related cellular senescence affects brain health and whether this phenomenon contributes to neuropathogenesis in PD is not yet fully understood. In this review, we highlight hallmarks of aging, including mitochondrial dysfunction, loss of proteostasis, genomic instability and telomere attrition in relation to well established PD neuropathological pathways. We then discuss the hallmarks of cellular senescence in the context of neuroscience and review studies that directly examine cellular senescence in PD. Studying senescence in PD presents challenges and holds promise for advancing our understanding of disease mechanisms, which could contribute to the development of effective disease-modifying therapeutics. Targeting senescent cells or modulating the senescence-associated secretory phenotype (SASP) in PD requires a comprehensive understanding of the complex relationship between PD pathogenesis and cellular senescence.
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Affiliation(s)
- Yue Ma
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Madalynn L Erb
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Darren J Moore
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
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Vialle RA, de Paiva Lopes K, Li Y, Ng B, Schneider JA, Buchman AS, Wang Y, Farfel JM, Barnes LL, Wingo AP, Wingo TS, Seyfried NT, De Jager PL, Gaiteri C, Tasaki S, Bennett DA. Structural variants linked to Alzheimer's Disease and other common age-related clinical and neuropathologic traits. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.08.12.24311887. [PMID: 39185527 PMCID: PMC11343262 DOI: 10.1101/2024.08.12.24311887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Advances have led to a greater understanding of the genetics of Alzheimer's Disease (AD). However, the gap between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data remains. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability. By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing around 20,000 common SVs from 1,088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's Disease and Related Disorders (AD/ADRD) clinical and pathologic traits were examined. Given the limited sample size, no genome-wide significant association was found, but we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with AD/ADRD phenotypes (nominal P < 0.05). The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene. This SV was in high LD with the respective AD GWAS locus and was associated with multiple AD/ADRD phenotypes, including tangle density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22 kb deletion associated with depression in ROSMAP and bearing similar association patterns as AD GWAS SNPs at the IQCK locus. In addition, genome-wide scans allowed the identification of 7 SVs, with no LD with SNPs and nominally associated with AD/ADRD traits. This result suggests potentially new ADRD risk loci not discoverable using SNP data. Among these findings, we highlight a 5.6 kb duplication of coding regions of the gene C1orf186 at chromosome 1 associated with indices of cognitive impairment, decline, and resilience. While further replication in independent datasets is needed to validate these findings, our results support the potential roles of common structural variations in the pathogenesis of AD/ADRD.
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Affiliation(s)
- Ricardo A Vialle
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Katia de Paiva Lopes
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Yan Li
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Bernard Ng
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Julie A Schneider
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Aron S Buchman
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Yanling Wang
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Jose M Farfel
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Lisa L Barnes
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Aliza P Wingo
- Department of Psychiatry, University of California, Davis CA, USA
- VA Northern California Health Care System, McClellan Park, CA, USA
| | - Thomas S Wingo
- Department of Neurology, University of California, Davis, CA, USA
| | - Nicholas T Seyfried
- Goizueta Alzheimer's Disease Research Center, Department of Neurology and Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Philip L De Jager
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY, USA
| | - Chris Gaiteri
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Shinya Tasaki
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
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Langerscheidt F, Wied T, Al Kabbani MA, van Eimeren T, Wunderlich G, Zempel H. Genetic forms of tauopathies: inherited causes and implications of Alzheimer's disease-like TAU pathology in primary and secondary tauopathies. J Neurol 2024; 271:2992-3018. [PMID: 38554150 PMCID: PMC11136742 DOI: 10.1007/s00415-024-12314-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 04/01/2024]
Abstract
Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.
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Affiliation(s)
- Felix Langerscheidt
- Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Tamara Wied
- Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
- Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Von-Liebig-Str. 20, 53359, Rheinbach, Germany
| | - Mohamed Aghyad Al Kabbani
- Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Thilo van Eimeren
- Multimodal Neuroimaging Group, Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany
- Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany
| | - Gilbert Wunderlich
- Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany
- Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Hans Zempel
- Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
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6
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Fujita M, Gao Z, Zeng L, McCabe C, White CC, Ng B, Green GS, Rozenblatt-Rosen O, Phillips D, Amir-Zilberstein L, Lee H, Pearse RV, Khan A, Vardarajan BN, Kiryluk K, Ye CJ, Klein HU, Wang G, Regev A, Habib N, Schneider JA, Wang Y, Young-Pearse T, Mostafavi S, Bennett DA, Menon V, De Jager PL. Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain. Nat Genet 2024; 56:605-614. [PMID: 38514782 DOI: 10.1038/s41588-024-01685-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/08/2024] [Indexed: 03/23/2024]
Abstract
The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.
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Affiliation(s)
- Masashi Fujita
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Zongmei Gao
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Lu Zeng
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Cristin McCabe
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Charles C White
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Bernard Ng
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Gilad Sahar Green
- Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Orit Rozenblatt-Rosen
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Genentech, South San Francisco, CA, USA
| | - Devan Phillips
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Genentech, South San Francisco, CA, USA
| | | | - Hyo Lee
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Richard V Pearse
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Atlas Khan
- Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Badri N Vardarajan
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY, USA
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Krzysztof Kiryluk
- Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Chun Jimmie Ye
- Institute for Human Genetics, University of California, San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Hans-Ulrich Klein
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Gao Wang
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY, USA
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Genentech, South San Francisco, CA, USA
| | - Naomi Habib
- Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Julie A Schneider
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Yanling Wang
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Tracy Young-Pearse
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Sara Mostafavi
- Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
- Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Vilas Menon
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Philip L De Jager
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
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7
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Landoulsi Z, Pachchek S, Bobbili DR, Pavelka L, May P, Krüger R. Genetic landscape of Parkinson's disease and related diseases in Luxembourg. Front Aging Neurosci 2023; 15:1282174. [PMID: 38173558 PMCID: PMC10761438 DOI: 10.3389/fnagi.2023.1282174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Objectives To explore the genetic architecture of PD in the Luxembourg Parkinson's Study including cohorts of healthy people and patients with Parkinson's disease (PD) and atypical parkinsonism (AP). Methods 809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes (LRRK2, SNCA, VPS35, PRKN, PARK7, PINK1 and ATP13A2). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs. Results We identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in LRRK2, PINK1 and PRKN. Eleven rare CNVs were detected in PRKN including seven duplications and four deletions. The majority of PRKN SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk. Conclusion We performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson's Study. Heterozygous SNVs and CNVs in PRKN were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare LRRK2 SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD.
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Affiliation(s)
- Zied Landoulsi
- LCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Sinthuja Pachchek
- LCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Dheeraj Reddy Bobbili
- LCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Lukas Pavelka
- Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg
- Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
| | - Patrick May
- LCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Rejko Krüger
- LCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg
- Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
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8
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Gasca-Salas C, Trompeta C, López-Aguirre M, Rodríguez Rojas R, Clarimon J, Dols-Icardo O, El Bounasri S, Guida P, Mata-Marín D, Hernández-Fernández F, Marras C, García-Cañamaque L, Plaza de Las Heras I, Obeso I, Vela L, Fernández-Rodríguez B. Brain hypometabolism in non-demented microtubule-associated protein tau H1 carriers with Parkinson's disease. J Neuroimaging 2023; 33:953-959. [PMID: 37726927 DOI: 10.1111/jon.13156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/10/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND AND PURPOSE The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype. METHODS We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late-onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a [18F]-Fluorodeoxyglucose PET-MR scan. RESULTS MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the [18F]-Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus. CONCLUSION PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.
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Affiliation(s)
- Carmen Gasca-Salas
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain
- University CEU-San Pablo, Madrid, Spain
| | - Clara Trompeta
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- PhD Program in Health Sciences, University of Alcala de Henares Alcalá de Henares, Madrid, Spain
| | - Miguel López-Aguirre
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain
- PhD Program in Physics, Complutense University of Madrid, Madrid, Spain
| | - Rafael Rodríguez Rojas
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain
| | - Jordi Clarimon
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain
- Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Oriol Dols-Icardo
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain
- Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Shaimaa El Bounasri
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain
- Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Pasqualina Guida
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- PhD Program in Neuroscience, Autónoma de Madrid University-Cajal Institute, Madrid, Spain
| | - David Mata-Marín
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- PhD Program in Neuroscience, Autónoma de Madrid University-Cajal Institute, Madrid, Spain
| | - Frida Hernández-Fernández
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Department of Nursing and Nutrition, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
| | - Connie Marras
- The Edmond J Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Lina García-Cañamaque
- Nuclear Medicine Department, PET-MRI Centre, HM Puerta del Sur University Hospital, HM Hospitales, Madrid, Spain
| | - Isabel Plaza de Las Heras
- Nuclear Medicine Department, PET-MRI Centre, HM Puerta del Sur University Hospital, HM Hospitales, Madrid, Spain
| | - Ignacio Obeso
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain
| | - Lydia Vela
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Department of Neurology, Hospital U Fundación Alcorcón, Calle Budapest, Alcorcón, Spain
| | - Beatriz Fernández-Rodríguez
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- PhD Program in Neuroscience, Autónoma de Madrid University-Cajal Institute, Madrid, Spain
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9
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Lee WP, Wang H, Dombroski B, Cheng PL, Tucci A, Si YQ, Farrell J, Tzeng JY, Leung YY, Malamon J, Wang LS, Vardarajan B, Farrer L, Schellenberg G. Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects. RESEARCH SQUARE 2023:rs.3.rs-3353179. [PMID: 37886469 PMCID: PMC10602095 DOI: 10.21203/rs.3.rs-3353179/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Structural variations (SVs) are important contributors to the genetics of human diseases. However, their role in Alzheimer's disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. We analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (N = 16,905) and identified 400,234 (168,223 high-quality) SVs. Laboratory validation yielded a sensitivity of 82% (85% for high-quality). We found a significant burden of deletions and duplications in AD cases, particularly for singletons and homozygous events. On AD genes, we observed the ultra-rare SVs associated with the disease, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1. Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, exemplified by a 5k deletion in complete LD with rs143080277 in NCK2. We also identified 16 SVs associated with AD and 13 SVs linked to AD-related pathological/cognitive endophenotypes. This study highlights the pivotal role of SVs in shaping our understanding of AD genetics.
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10
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Lepinay E, Cicchetti F. Tau: a biomarker of Huntington's disease. Mol Psychiatry 2023; 28:4070-4083. [PMID: 37749233 DOI: 10.1038/s41380-023-02230-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 07/31/2023] [Accepted: 08/11/2023] [Indexed: 09/27/2023]
Abstract
Developing effective treatments for patients with Huntington's disease (HD)-a neurodegenerative disorder characterized by severe cognitive, motor and psychiatric impairments-is proving extremely challenging. While the monogenic nature of this condition enables to identify individuals at risk, robust biomarkers would still be extremely valuable to help diagnose disease onset and progression, and especially to confirm treatment efficacy. If measurements of cerebrospinal fluid neurofilament levels, for example, have demonstrated use in recent clinical trials, other proteins may prove equal, if not greater, relevance as biomarkers. In fact, proteins such as tau could specifically be used to detect/predict cognitive affectations. We have herein reviewed the literature pertaining to the association between tau levels and cognitive states, zooming in on Alzheimer's disease, Parkinson's disease and traumatic brain injury in which imaging, cerebrospinal fluid, and blood samples have been interrogated or used to unveil a strong association between tau and cognition. Collectively, these areas of research have accrued compelling evidence to suggest tau-related measurements as both diagnostic and prognostic tools for clinical practice. The abundance of information retrieved in this niche of study has laid the groundwork for further understanding whether tau-related biomarkers may be applied to HD and guide future investigations to better understand and treat this disease.
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Affiliation(s)
- Eva Lepinay
- Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada
- Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, Canada
| | - Francesca Cicchetti
- Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec, QC, Canada.
- Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, Canada.
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11
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Wang H, Dombroski BA, Cheng PL, Tucci A, Si YQ, Farrell JJ, Tzeng JY, Leung YY, Malamon JS, Wang LS, Vardarajan BN, Farrer LA, Schellenberg GD, Lee WP. Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.09.13.23295505. [PMID: 37745545 PMCID: PMC10516060 DOI: 10.1101/2023.09.13.23295505] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer's disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05, P=0.03), particularly for singletons (OR=1.12, P=0.0002) and homozygous events (OR=1.10, P<0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1, were associated with AD (SKAT-O P=0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R2=0.99) with rs143080277 (chr2:105749599) in NCK2. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.
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Affiliation(s)
- Hui Wang
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
| | - Beth A Dombroski
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
| | - Po-Liang Cheng
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
| | - Albert Tucci
- Bioinformatics Research Center, North Carolina State University, NC 27695, USA
| | - Ya-Qin Si
- Bioinformatics Research Center, North Carolina State University, NC 27695, USA
| | - John J Farrell
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, MA 02118, USA
| | - Jung-Ying Tzeng
- Bioinformatics Research Center, North Carolina State University, NC 27695, USA
| | - Yuk Yee Leung
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
| | - John S Malamon
- Department of Surgery, Scholl of Medicine, University of Colorado, CO 80045, USA
| | - Li-San Wang
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
| | - Badri N Vardarajan
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, NY 10032, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, NY 10032, USA
| | - Lindsay A Farrer
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, MA 02118, USA
- Department of Neurology, Boston University School of Medicine, MA 02118, USA
- Department of Ophthalmology, Boston University School of Medicine, MA 02118, USA
- Department of Biostatistics, Boston University School of Public Health, MA 02118, USA
- Department of Epidemiology, Boston University School of Public Health, MA 02118, USA
| | - Gerard D Schellenberg
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
| | - Wan-Ping Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
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12
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Wang H, Makowski C, Zhang Y, Qi A, Kaufmann T, Smeland OB, Fiecas M, Yang J, Visscher PM, Chen CH. Chromosomal inversion polymorphisms shape human brain morphology. Cell Rep 2023; 42:112896. [PMID: 37505983 PMCID: PMC10508191 DOI: 10.1016/j.celrep.2023.112896] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 06/27/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
The impact of chromosomal inversions on human brain morphology remains underexplored. We studied 35 common inversions classified from genotypes of 33,018 adults with European ancestry. The inversions at 2p22.3, 16p11.2, and 17q21.31 reach genome-wide significance, followed by 8p23.1 and 6p21.33, in their association with cortical and subcortical morphology. The 17q21.31, 8p23.1, and 16p11.2 regions comprise the LRRC37, OR7E, and NPIP duplicated gene families. We find the 17q21.31 MAPT inversion region, known for harboring neurological risk, to be the most salient locus among common variants for shaping and patterning the cortex. Overall, we observe the inverted orientations decreasing brain size, with the exception that the 2p22.3 inversion is associated with increased subcortical volume and the 8p23.1 inversion is associated with increased motor cortex. These significant inversions are in the genomic hotspots of neuropsychiatric loci. Our findings are generalizable to 3,472 children and demonstrate inversions as essential genetic variation to understand human brain phenotypes.
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Affiliation(s)
- Hao Wang
- Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA
| | - Carolina Makowski
- Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA
| | - Yanxiao Zhang
- Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China
| | - Anna Qi
- Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA
| | - Tobias Kaufmann
- Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, 72076 Tübingen, Germany; Norwegian Centre for Mental Disorders Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway
| | - Olav B Smeland
- Norwegian Centre for Mental Disorders Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway
| | - Mark Fiecas
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA
| | - Jian Yang
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China
| | - Peter M Visscher
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Chi-Hua Chen
- Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92093, USA.
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13
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Tauber CV, Schwarz SC, Rösler TW, Arzberger T, Gentleman S, Windl O, Krumbiegel M, Reis A, Ruf VC, Herms J, Höglinger GU. Different MAPT haplotypes influence expression of total MAPT in postmortem brain tissue. Acta Neuropathol Commun 2023; 11:40. [PMID: 36906636 PMCID: PMC10008602 DOI: 10.1186/s40478-023-01534-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/21/2023] [Indexed: 03/13/2023] Open
Abstract
The MAPT gene, encoding the microtubule-associated protein tau on chromosome 17q21.31, is result of an inversion polymorphism, leading to two allelic variants (H1 and H2). Homozygosity for the more common haplotype H1 is associated with an increased risk for several tauopathies, but also for the synucleinopathy Parkinson's disease (PD). In the present study, we aimed to clarify whether the MAPT haplotype influences expression of MAPT and SNCA, encoding the protein α-synuclein (α-syn), on mRNA and protein levels in postmortem brains of PD patients and controls. We also investigated mRNA expression of several other MAPT haplotype-encoded genes. Postmortem tissues from cortex of fusiform gyrus (ctx-fg) and of the cerebellar hemisphere (ctx-cbl) of neuropathologically confirmed PD patients (n = 95) and age- and sex-matched controls (n = 81) were MAPT haplotype genotyped to identify cases homozygous for either H1 or H2. Relative expression of genes was quantified using real-time qPCR; soluble and insoluble protein levels of tau and α-syn were determined by Western blotting. Homozygosity for H1 versus H2 was associated with increased total MAPT mRNA expression in ctx-fg regardless of disease state. Inversely, H2 homozygosity was associated with markedly increased expression of the corresponding antisense MAPT-AS1 in ctx-cbl. PD patients had higher levels of insoluble 0N3R and 1N4R tau isoforms regardless of the MAPT genotype. The increased presence of insoluble α-syn in PD patients in ctx-fg validated the selected postmortem brain tissue. Our findings in this small, but well controlled cohort of PD and controls support a putative biological relevance of tau in PD. However, we did not identify any link between the disease-predisposing H1/H1 associated overexpression of MAPT with PD status. Further studies are required to gain a deeper understanding of the potential regulatory role of MAPT-AS1 and its association to the disease-protective H2/H2 condition in the context of PD.
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Affiliation(s)
- Christina V Tauber
- Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Department of Neurology, School of Medicine, Technical University Munich, Munich, Germany.,Department of Obstetrics and Gynecology, Ludiwgs-Maximilians University of Munich, Munich, Germany
| | - Sigrid C Schwarz
- Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Thomas W Rösler
- Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Department of Neurology, School of Medicine, Technical University Munich, Munich, Germany
| | - Thomas Arzberger
- Center for Neuropathology and Prion Research, Ludwig-Maximilians University of Munich, Munich, Germany.,Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University, Munich, Germany
| | - Steve Gentleman
- Parkinson's UK Brain Bank, Department of Brain Sciences, Imperial College London, London, UK.,Neuropathology Unit, Department of Brain Sciences, Department of Medicine, Imperial College London, London, UK
| | - Otto Windl
- Center for Neuropathology and Prion Research, Ludwig-Maximilians University of Munich, Munich, Germany
| | - Mandy Krumbiegel
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - André Reis
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Viktoria C Ruf
- Center for Neuropathology and Prion Research, Ludwig-Maximilians University of Munich, Munich, Germany
| | - Jochen Herms
- Center for Neuropathology and Prion Research, Ludwig-Maximilians University of Munich, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Günter U Höglinger
- Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. .,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. .,Department of Neurology, Ludwig-Maximilians University of Munich, Munich, Germany.
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14
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Wang H, Wang LS, Schellenberg G, Lee WP. The role of structural variations in Alzheimer's disease and other neurodegenerative diseases. Front Aging Neurosci 2023; 14:1073905. [PMID: 36846102 PMCID: PMC9944073 DOI: 10.3389/fnagi.2022.1073905] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/31/2022] [Indexed: 02/10/2023] Open
Abstract
Dozens of single nucleotide polymorphisms (SNPs) related to Alzheimer's disease (AD) have been discovered by large scale genome-wide association studies (GWASs). However, only a small portion of the genetic component of AD can be explained by SNPs observed from GWAS. Structural variation (SV) can be a major contributor to the missing heritability of AD; while SV in AD remains largely unexplored as the accurate detection of SVs from the widely used array-based and short-read technology are still far from perfect. Here, we briefly summarized the strengths and weaknesses of available SV detection methods. We reviewed the current landscape of SV analysis in AD and SVs that have been found associated with AD. Particularly, the importance of currently less explored SVs, including insertions, inversions, short tandem repeats, and transposable elements in neurodegenerative diseases were highlighted.
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Affiliation(s)
- Hui Wang
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Li-San Wang
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Gerard Schellenberg
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Wan-Ping Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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15
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Bowles KR, Pugh DA, Liu Y, Patel T, Renton AE, Bandres-Ciga S, Gan-Or Z, Heutink P, Siitonen A, Bertelsen S, Cherry JD, Karch CM, Frucht SJ, Kopell BH, Peter I, Park YJ, Charney A, Raj T, Crary JF, Goate AM. 17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease are associated with LRRC37A/2 expression in astrocytes. Mol Neurodegener 2022; 17:48. [PMID: 35841044 PMCID: PMC9284779 DOI: 10.1186/s13024-022-00551-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 06/21/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Parkinson's disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. METHODS To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. RESULTS We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. CONCLUSION These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.
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Affiliation(s)
- Kathryn R. Bowles
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Derian A. Pugh
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Yiyuan Liu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Tulsi Patel
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Alan E. Renton
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Sara Bandres-Ciga
- Laboratory of Neurogenetics, National Institute On Aging, National Institutes of Health, Bethesda, MD USA
| | - Ziv Gan-Or
- Department of Human Genetics, McGill University, Montréal, Québec Canada
- The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Québec Canada
- Department of Neurology and Neurosurgery, McGill University, Montréal, Québec Canada
| | - Peter Heutink
- Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Ari Siitonen
- Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland
- Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland
| | - Sarah Bertelsen
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Jonathan D. Cherry
- Alzheimer’s Disease and CTE Center, Boston University, Boston University School of Medicine, Boston, MA USA
- Department of Neurology, Boston University School of Medicine, Boston, MA USA
- VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA USA
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA USA
| | - Celeste M. Karch
- Department of Psychiatry, Washington University in St Louis, St. Louis, MO USA
| | - Steven J. Frucht
- Department of Neurology, Fresco Institute for Parkinson’s and Movement Disorders, New York University Langone, New York, NY USA
| | - Brian H. Kopell
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Center for Neuromodulation, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Inga Peter
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Y. J. Park
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | | | - Alexander Charney
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Towfique Raj
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - John F. Crary
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - A. M. Goate
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
- Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY USA
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16
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Tarozzi M, Bartoletti-Stella A, Dall'Olio D, Matteuzzi T, Baiardi S, Parchi P, Castellani G, Capellari S. Identification of recurrent genetic patterns from targeted sequencing panels with advanced data science: a case-study on sporadic and genetic neurodegenerative diseases. BMC Med Genomics 2022; 15:26. [PMID: 35144616 PMCID: PMC8830183 DOI: 10.1186/s12920-022-01173-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 02/02/2022] [Indexed: 11/10/2022] Open
Abstract
Background Targeted Next Generation Sequencing is a common and powerful approach used in both clinical and research settings. However, at present, a large fraction of the acquired genetic information is not used since pathogenicity cannot be assessed for most variants. Further complicating this scenario is the increasingly frequent description of a poli/oligogenic pattern of inheritance showing the contribution of multiple variants in increasing disease risk. We present an approach in which the entire genetic information provided by target sequencing is transformed into binary data on which we performed statistical, machine learning, and network analyses to extract all valuable information from the entire genetic profile. To test this approach and unbiasedly explore the presence of recurrent genetic patterns, we studied a cohort of 112 patients affected either by genetic Creutzfeldt–Jakob (CJD) disease caused by two mutations in the PRNP gene (p.E200K and p.V210I) with different penetrance or by sporadic Alzheimer disease (sAD). Results Unsupervised methods can identify functionally relevant sources of variation in the data, like haplogroups and polymorphisms that do not follow Hardy–Weinberg equilibrium, such as the NOTCH3 rs11670823 (c.3837 + 21 T > A). Supervised classifiers can recognize clinical phenotypes with high accuracy based on the mutational profile of patients. In addition, we found a similar alteration of allele frequencies compared the European population in sporadic patients and in V210I-CJD, a poorly penetrant PRNP mutation, and sAD, suggesting shared oligogenic patterns in different types of dementia. Pathway enrichment and protein–protein interaction network revealed different altered pathways between the two PRNP mutations. Conclusions We propose this workflow as a possible approach to gain deeper insights into the genetic information derived from target sequencing, to identify recurrent genetic patterns and improve the understanding of complex diseases. This work could also represent a possible starting point of a predictive tool for personalized medicine and advanced diagnostic applications. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01173-4.
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Affiliation(s)
- M Tarozzi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - A Bartoletti-Stella
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.,IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
| | - D Dall'Olio
- Department of Physics and Astronomy, University of Bologna, Bologna, Italy
| | - T Matteuzzi
- Department of Physics and Astronomy, University of Bologna, Bologna, Italy
| | - S Baiardi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.,IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
| | - P Parchi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.,IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
| | - G Castellani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
| | - S Capellari
- IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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17
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Su X, Li W, Lv L, Li X, Yang J, Luo XJ, Liu J. Transcriptome-Wide Association Study Provides Insights Into the Genetic Component of Gene Expression in Anxiety. Front Genet 2021; 12:740134. [PMID: 34650599 PMCID: PMC8505959 DOI: 10.3389/fgene.2021.740134] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 09/15/2021] [Indexed: 01/10/2023] Open
Abstract
Anxiety disorders are common mental disorders that often result in disability. Recently, large-scale genome-wide association studies (GWASs) have identified several novel risk variants and loci for anxiety disorders (or anxiety traits). Nevertheless, how the reported risk variants confer risk of anxiety remains unknown. To identify genes whose cis-regulated expression levels are associated with risk of anxiety traits, we conducted a transcriptome-wide association study (TWAS) by integrating genome-wide associations from a large-scale GWAS (N = 175,163) (which evaluated anxiety traits based on Generalized Anxiety Disorder 2-item scale (GAD-2) score) and brain expression quantitative trait loci (eQTL) data (from the PsychENCODE and GTEx). We identified 19 and 17 transcriptome-wide significant (TWS) genes in the PsychENCODE and GTEx, respectively. Intriguingly, 10 genes showed significant associations with anxiety in both datasets, strongly suggesting that genetic risk variants may confer risk of anxiety traits by regulating the expression of these genes. Top TWS genes included RNF123, KANSL1-AS1, GLYCTK, CRHR1, DND1P1, MAPT and ARHGAP27. Of note, 25 TWS genes were not implicated in the original GWAS. Our TWAS identified 26 risk genes whose cis-regulated expression were significantly associated with anxiety, providing important insights into the genetic component of gene expression in anxiety disorders/traits and new clues for future drug development.
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Affiliation(s)
- Xi Su
- Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Wenqiang Li
- Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Luxian Lv
- Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.,Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, China
| | - Xiaoyan Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Jinfeng Yang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China
| | - Xiong-Jian Luo
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.,KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Jiewei Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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18
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Leveille E, Ross OA, Gan-Or Z. Tau and MAPT genetics in tauopathies and synucleinopathies. Parkinsonism Relat Disord 2021; 90:142-154. [PMID: 34593302 PMCID: PMC9310195 DOI: 10.1016/j.parkreldis.2021.09.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/25/2021] [Accepted: 09/09/2021] [Indexed: 10/20/2022]
Abstract
MAPT encodes the microtubule-associated protein tau, which is the main component of neurofibrillary tangles (NFTs) and found in other protein aggregates. These aggregates are among the pathological hallmarks of primary tauopathies such as frontotemporal dementia (FTD). Abnormal tau can also be observed in secondary tauopathies such as Alzheimer's disease (AD) and synucleinopathies such as Parkinson's disease (PD). On top of pathological findings, genetic data also links MAPT to these disorders. MAPT variations are a cause or risk factors for many tauopathies and synucleinopathies and are associated with certain clinical and pathological features in affected individuals. In addition to clinical, pathological, and genetic overlap, evidence also suggests that tau and alpha-synuclein may interact on the molecular level, and thus might collaborate in the neurodegenerative process. Understanding the role of MAPT variations in tauopathies and synucleinopathies is therefore essential to elucidate the role of tau in the pathogenesis and phenotype of those disorders, and ultimately to develop targeted therapies. In this review, we describe the role of MAPT genetic variations in tauopathies and synucleinopathies, several genotype-phenotype and pathological features, and discuss their implications for the classification and treatment of those disorders.
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Affiliation(s)
| | - Owen A Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Ziv Gan-Or
- The Neuro (Montreal Neurological Institute-hospital), McGill University, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
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19
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Strauß T, Marvian-Tayaranian A, Sadikoglou E, Dhingra A, Wegner F, Trümbach D, Wurst W, Heutink P, Schwarz SC, Höglinger GU. iPS Cell-Based Model for MAPT Haplotype as a Risk Factor for Human Tauopathies Identifies No Major Differences in TAU Expression. Front Cell Dev Biol 2021; 9:726866. [PMID: 34532319 PMCID: PMC8438159 DOI: 10.3389/fcell.2021.726866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/09/2021] [Indexed: 11/13/2022] Open
Abstract
The H1 haplotype of the microtubule-associated protein tau (MAPT) gene is a common genetic risk factor for some neurodegenerative diseases such as progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease. The molecular mechanism causing the increased risk for the named diseases, however, remains unclear. In this paper, we present a valuable tool of eight small molecule neural precursor cell lines (smNPC) homozygous for the MAPT haplotypes (four H1/H1 and four H2/H2 cell lines), which can be used to identify MAPT-dependent phenotypes. The employed differentiation protocol is fast due to overexpression of NEUROGENIN-2 and therefore suitable for high-throughput approaches. A basic characterization of all human cell lines was performed, and their TAU and α-SYNUCLEIN profiles were compared during a differentiation time of 30 days. We could identify higher levels of conformationally altered TAU in cell lines carrying the H2 haplotype. Additionally, we found increased expression levels of α-SYNUCLEIN in H1/H1 cells. With this resource, we aim to fill a gap in neurodegenerative disease modeling with induced pluripotent stem cells (iPSC) for sporadic tauopathies.
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Affiliation(s)
- Tabea Strauß
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Department of Neurology, Technical University Munich, Munich, Germany
| | - Amir Marvian-Tayaranian
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Department of Neurology, Technical University Munich, Munich, Germany
| | - Eldem Sadikoglou
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Ashutosh Dhingra
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - Florian Wegner
- Department of Neurology, Hanover Medical School, Hanover, Germany
- Center for Systems Neuroscience, Hanover, Germany
| | - Dietrich Trümbach
- Institute of Developmental Genetics, Helmholtz Zentrum München, Oberschleißheim, Germany
| | - Wolfgang Wurst
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Institute of Developmental Genetics, Helmholtz Zentrum München, Oberschleißheim, Germany
- TUM School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Peter Heutink
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Sigrid C. Schwarz
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Department of Neurology, Technical University Munich, Munich, Germany
- Geriatric Clinic Haag, Haag in Oberbayern, Germany
| | - Günter U. Höglinger
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Department of Neurology, Technical University Munich, Munich, Germany
- Department of Neurology, Hanover Medical School, Hanover, Germany
- Center for Systems Neuroscience, Hanover, Germany
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20
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Grenn FP, Moore A, Bandres-Ciga S, Krohn L, Blauwendraat C. Assessment of ANG variants in Parkinson's disease. Neurobiol Aging 2021; 104:111.e1-111.e4. [PMID: 33875291 PMCID: PMC8225568 DOI: 10.1016/j.neurobiolaging.2021.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/01/2020] [Accepted: 03/09/2021] [Indexed: 11/23/2022]
Abstract
Genetic risk factors are occasionally shared between different neurodegenerative diseases. Previous studies have linked ANG, a gene encoding angiogenin, to both Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Functional studies suggest ANG plays a neuroprotective role in both PD and amyotrophic lateral sclerosis by reducing cell death. We further explored the genetic association between ANG and PD by analyzing genotype data from the International Parkinson's Disease Genomics Consortium (14,671 cases and 17,667 controls) and whole genome sequencing data from the Accelerating Medicines Partnership - Parkinson's disease initiative (AMP-PD, https://amp-pd.org/) (1,647 cases and 1,050 controls). Our analysis did not replicate the findings of previous studies and identified no significant association between ANG variants and PD risk.
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Affiliation(s)
- Francis P Grenn
- Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
| | - Anni Moore
- Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
| | - Sara Bandres-Ciga
- Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
| | - Lynne Krohn
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Cornelis Blauwendraat
- Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
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21
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Kanaya Y, Kume K, Morino H, Ohsawa R, Kurashige T, Kamada M, Torii T, Izumi Y, Maruyama H, Kawakami H. Analysis of genetic risk factors in Japanese patients with Parkinson's disease. J Hum Genet 2021; 66:957-964. [PMID: 33742109 DOI: 10.1038/s10038-021-00910-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 11/09/2022]
Abstract
Parkinson's disease (PD) is caused by a combination of genetic and environmental factors. Notably, genetic risk factors vary according to ethnicity and geographical regions, and few studies have analyzed the frequency of PD causative genes in Japanese patients. Therefore, we performed genetic analyses of Japanese patients with PD. We recruited 221 participants, including 26 patients with familial PD. Genetic risk factors were evaluated by target sequencing and gene dosage analysis. We detected the genetic risk factors in 58 cases (26.2%) and classified patients into three groups to clarify the differences in genetic risk factors by age at onset (AAO). The early-onset group (AAO < 50 years) included 18 cases (44.7%), who tended to have a larger number of genetic risk factors than the later-onset groups. Regarding the AAO for each causative gene, patients with PRKN variants were significantly younger at onset than those bearing LRRK2 variants. LRRK2 variants showed similar frequency in each AAO group. Of note, we identified two novel variants. Patients with early-onset PD have more genetic risk factors than patients with late-onset PD. In Japanese patients with PD, PRKN, and LRRK2 were the major PD-related genes. Particularly, LRRK2 was a common genetic factor in all age groups because of the presence of the Asian-specific variant such as LRRK2 p.G2385R. Accumulation of genetic and clinical data can contribute to the development of treatments for PD.
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Affiliation(s)
- Yuhei Kanaya
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.,Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Kodai Kume
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Hiroyuki Morino
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. .,Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
| | - Ryosuke Ohsawa
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takashi Kurashige
- Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Masaki Kamada
- Department of Gastroenterology & Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsuyoshi Torii
- Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Yuishin Izumi
- Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hirofumi Maruyama
- Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Hideshi Kawakami
- Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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Holbrook JA, Jarosz-Griffiths HH, Caseley E, Lara-Reyna S, Poulter JA, Williams-Gray CH, Peckham D, McDermott MF. Neurodegenerative Disease and the NLRP3 Inflammasome. Front Pharmacol 2021; 12:643254. [PMID: 33776778 PMCID: PMC7987926 DOI: 10.3389/fphar.2021.643254] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/22/2021] [Indexed: 12/13/2022] Open
Abstract
The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.
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Affiliation(s)
- Jonathan A. Holbrook
- Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
| | - Heledd H. Jarosz-Griffiths
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, United Kingdom
- Leeds Institute of Medical Research at St. James’s University Hospital, Leeds, United Kingdom
- Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
| | - Emily Caseley
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, United Kingdom
- Leeds Institute of Medical Research at St. James’s University Hospital, Leeds, United Kingdom
| | - Samuel Lara-Reyna
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
| | - James A. Poulter
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, United Kingdom
- Leeds Institute of Medical Research at St. James’s University Hospital, Leeds, United Kingdom
| | - Caroline H. Williams-Gray
- Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
| | - Daniel Peckham
- Leeds Institute of Medical Research at St. James’s University Hospital, Leeds, United Kingdom
- Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
- Leeds Centre for Cystic Fibrosis, St James’s University Hospital, Leeds, United Kingdom
| | - Michael F. McDermott
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, United Kingdom
- Leeds Cystic Fibrosis Trust Strategic Research Centre, University of Leeds, Leeds, United Kingdom
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A Specific Diplotype H1j/H2 of the MAPT Gene Could Be Responsible for Parkinson's Disease with Dementia. Case Rep Genet 2020; 2020:8813344. [PMID: 33343949 PMCID: PMC7732378 DOI: 10.1155/2020/8813344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 11/15/2020] [Accepted: 11/20/2020] [Indexed: 11/17/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. Five to ten percent of patients have monogenic form of the disease, while most of sporadic PD cases are caused by the combination of genetic and environmental factors. Microtubule-associated protein tau (MAPT) has been appointed as one of the most important risk factors for several neurodegenerative diseases including PD. MAPT is characterized by an inversion in chromosome 17 resulting in two distinct haplotypes H1 and H2. Studies described a significant association of MAPT H1j subhaplotype with PD risk, while H2 haplotype was associated with Parkinsonism, particularly to its bradykinetic component. We report here an isolated case displaying an akinetic-rigid form of PD, with age of onset of 41 years and a good response to levodopa, who developed dementia gradually during the seven years of disease progression. The patient does not carry the LRRK2 G2019S mutation, copy number variations, nor pathogenic and rare variants in known genes associated with PD. MAPT subhaplotype genotyping revealed that the patient has the H1j/H2 diplotype, his mother H1j/H1j, his two healthy brothers H1j/H1v and his deceased father was by deduction H1v/H2. The H1j/H2 diplotype was shown in a total of 3 PD patients among 80, who also did not have known PD-causing mutation and in 1 out of 92 healthy individual controls. The three patients with this diplotype all have a similar clinical phenotype. Our results suggest that haplotypes H1j and H2 are strong risk factor alleles, and their combination could be responsible for early onset of PD with dementia.
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Deutschlander AB, Konno T, Soto‐Beasley AI, Walton RL, van Gerpen JA, Uitti RJ, Heckman MG, Wszolek ZK, Ross OA. Association of MAPT subhaplotypes with clinical and demographic features in Parkinson's disease. Ann Clin Transl Neurol 2020; 7:1557-1563. [PMID: 32767721 PMCID: PMC7480915 DOI: 10.1002/acn3.51139] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/24/2020] [Accepted: 06/25/2020] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE To determine whether distinct microtubule-associated protein tau MAPT H1 subhaplotypes are associated with clinical and demographic features in Parkinson's disease. METHODS A retrospective cohort study included 855 unrelated Caucasian patients with Parkinson's disease who were seen by Movement Disorder specialists at the Mayo Clinic Florida between 1998 and 2016. The primary outcome measures were specific demographic and clinical features of Parkinson's disease, including age at onset, disease progression, survival, motor signs, dementia, dystonia, dyskinesia, autonomic dysfunction, impulse control disorder, psychiatric features, REM sleep behavior disorder, restless legs syndrome, and Parkinson's disease subtype. Specific clinical features were measured at the initial visit and most recent visit. These outcomes were assessed for association with MAPT H1 subhaplotypes, which were defined by six haplotype tagging variants. RESULTS Median onset age was 64 years (range: 22-94 years); 548 (64%) of patients were male. Significant associations (P < 0.0029) were observed between MAPT H1b and orthostatic hypotension (OR = 1.72, P = 0.001); between H1j and rest tremor (OR = 0.15; P < 0.001) as well as REM sleep behavior disorder (OR = 3.87, P < 0.001); between H1r and bradykinesia (OR = 0.11; P < 0.001); and between H1v and restless legs syndrome (OR = 4.02, P = 0.002). INTERPRETATION Four MAPT H1 subhaplotypes, but not the H2 haplotype, were significantly associated with specific clinical features in Parkinson's disease. MAPT haplotypic structure may explain some of the phenotypic variability in disease. Replication of our findings will be critical to fully resolve the Parkinson's disease risk association signal at Chr17q21.
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Affiliation(s)
- Angela B. Deutschlander
- Department of NeurologyMayo ClinicJacksonvilleFlorida
- Department of NeuroscienceMayo ClinicJacksonvilleFlorida
| | - Takuya Konno
- Department of NeurologyMayo ClinicJacksonvilleFlorida
- Department of NeurologyBrain Research InstituteNiigata UniversityNiigataJapan
| | | | | | | | - Ryan J. Uitti
- Department of NeurologyMayo ClinicJacksonvilleFlorida
| | - Michael G. Heckman
- Division of Biomedical Statistics and InformaticsMayo ClinicJacksonvilleFlorida
| | | | - Owen A. Ross
- Department of NeuroscienceMayo ClinicJacksonvilleFlorida
- Department of Clinical GenomicsMayo ClinicJacksonvilleFlorida
- Neuroscience TrackMayo Graduate SchoolMayo ClinicJacksonvilleFlorida
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Abstract
Highlights In the current review, we thoroughly reviewed 74 identified articles regarding genes and genetic loci that confer susceptibility to ET. Over 50 genes/genetic loci have been examined for possible association with ET, but consistent results failed to be reported raising the need for collaborative multiethnic studies. Background: Essential tremor (ET) is a common movement disorder, which is mainly characterized by bilateral tremor (postural and/or kinetic) in the upper limbs, with other parts of the body possibly involved. While the pathophysiology of ET is still unclear, there is accumulating evidence indicating that genetic variability may be heavily involved in ET pathogenesis. This review focuses on the role of genetic risk factors in ET susceptibility. Methods: The PubMed database was searched for articles written in English, for studies with humans with ET, controls without ET, and genetic variants. The terms “essential tremor” and “polymorphism” (as free words) were used during search. We also performed meta-analyses for the most examined genetic variants. Results: Seventy four articles concerning LINGO1, LINGO2, LINGO4, SLC1A2, STK32B, PPARGC1A, CTNNA3, DRD3, ALAD, VDR, HMOX1, HMOX2, LRRK1,LRRK2, GBA, SNCA, MAPT, FUS, CYPsIL17A, IL1B, NOS1, ADH1B, TREM2, RIT2, HNMT, MTHFR, PPP2R2B, GSTP1, PON1, GABA receptors and GABA transporter, HS1BP3, ADH2, hSKCa3 and CACNL1A4 genes, and ETM genetic loci were included in the current review. Results from meta-analyses revealed a marginal association for the STK32B rs10937625 and a marginal trend for association (in sensitivity analysis) for the LINGO1 rs9652490, with ET. Discussion: Quite a few variants have been examined for their possible association with ET. LINGO1 rs9652490 and STK32B rs10937625 appear to influence, to some extent, ET susceptibility. However, the conflicting results and the lack of replication for many candidate genes raise the need for collaborative multiethnic studies.
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Mangone G, Bekadar S, Cormier-Dequaire F, Tahiri K, Welaratne A, Czernecki V, Pineau F, Karachi C, Castrioto A, Durif F, Tranchant C, Devos D, Thobois S, Meissner WG, Navarro MS, Cornu P, Lesage S, Brice A, Welter ML, Corvol JC. Early cognitive decline after bilateral subthalamic deep brain stimulation in Parkinson's disease patients with GBA mutations. Parkinsonism Relat Disord 2020; 76:56-62. [PMID: 32866938 DOI: 10.1016/j.parkreldis.2020.04.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/25/2020] [Accepted: 04/03/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles. OBJECTIVE To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS. METHODS Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes. RESULTS We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (β = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups. CONCLUSION GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.
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Affiliation(s)
- Graziella Mangone
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France
| | - Samir Bekadar
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France
| | - Florence Cormier-Dequaire
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France
| | - Khadija Tahiri
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France
| | - Arlette Welaratne
- Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France
| | - Virginie Czernecki
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Institut of Memory and Alzheimer's Disease (IM2A), Paris, France
| | - Fanny Pineau
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Institut of Memory and Alzheimer's Disease (IM2A), Paris, France
| | - Carine Karachi
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurochirurgie, Paris, France
| | - Anna Castrioto
- Unité des Troubles du Mouvement, Département de Neurologie, CHU de Grenoble, Université de Grenoble Alpes, INSERM U1216, F-38000, Grenoble, France
| | - Frank Durif
- Service de Neurologie, CHU Clermont-Ferrand, Université Clermont Auvergne, F-63000, Clermont-Ferrand, France
| | - Christine Tranchant
- Département de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - David Devos
- Département de Neurologie, Centre Expert maladie de Parkinson, Département de Pharmacologie Clinique et des Neurosciences, Université de Lille, Centre Hospitalier Universitaire de Lille, INSERM UMR_S 1171, LICEND, France
| | - Stéphane Thobois
- Neurologie C, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69500, Bron, France; Univ Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Sud, Lyon, France; Institut des Sciences Cognitives Marc Jeannerod, UMR 5229, CNRS, Bron, France
| | - Wassilios G Meissner
- Service de Neurologie, Centre Expert Parkinson, IMNc, CHU Bordeaux, 33000, Bordeaux, France; Univ. de Bordeaux, Institut des Maladies Neurodégénératives, CNRS, UMR 5293, 33000, Bordeaux, France; Dept. Medicine, University of Otago, Christchurch, New Zealand; Brain Research Institute, Christchurch, New Zealand
| | - Maria Soledad Navarro
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurochirurgie, Paris, France
| | - Philippe Cornu
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurochirurgie, Paris, France
| | - Suzanne Lesage
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France
| | - Alexis Brice
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France
| | - Marie Laure Welter
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France; Département de Neurophysiologie, CHU Rouen, Université de Normandie, Rouen, France
| | - Jean-Christophe Corvol
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Clinical Research Center Neurosciences, Paris, France.
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González JR, Ruiz-Arenas C, Cáceres A, Morán I, López-Sánchez M, Alonso L, Tolosana I, Guindo-Martínez M, Mercader JM, Esko T, Torrents D, González J, Pérez-Jurado LA. Polymorphic Inversions Underlie the Shared Genetic Susceptibility of Obesity-Related Diseases. Am J Hum Genet 2020; 106:846-858. [PMID: 32470372 DOI: 10.1016/j.ajhg.2020.04.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/28/2020] [Indexed: 11/25/2022] Open
Abstract
The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.
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28
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Giner-Delgado C, Villatoro S, Lerga-Jaso J, Gayà-Vidal M, Oliva M, Castellano D, Pantano L, Bitarello BD, Izquierdo D, Noguera I, Olalde I, Delprat A, Blancher A, Lalueza-Fox C, Esko T, O'Reilly PF, Andrés AM, Ferretti L, Puig M, Cáceres M. Evolutionary and functional impact of common polymorphic inversions in the human genome. Nat Commun 2019; 10:4222. [PMID: 31530810 PMCID: PMC6748972 DOI: 10.1038/s41467-019-12173-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 08/27/2019] [Indexed: 12/21/2022] Open
Abstract
Inversions are one type of structural variants linked to phenotypic differences and adaptation in multiple organisms. However, there is still very little information about polymorphic inversions in the human genome due to the difficulty of their detection. Here, we develop a new high-throughput genotyping method based on probe hybridization and amplification, and we perform a complete study of 45 common human inversions of 0.1–415 kb. Most inversions promoted by homologous recombination occur recurrently in humans and great apes and they are not tagged by SNPs. Furthermore, there is an enrichment of inversions showing signatures of positive or balancing selection, diverse functional effects, such as gene disruption and gene-expression changes, or association with phenotypic traits. Therefore, our results indicate that the genome is more dynamic than previously thought and that human inversions have important functional and evolutionary consequences, making possible to determine for the first time their contribution to complex traits. Inversions are a little-studied type of genomic variation that could contribute to phenotypic traits. Here the authors characterize 45 common polymorphic inversions in human populations and investigate their evolutionary and functional impact.
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Affiliation(s)
- Carla Giner-Delgado
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain.,Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Sergi Villatoro
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Jon Lerga-Jaso
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Magdalena Gayà-Vidal
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain.,CIBIO/InBIO Research Center in Biodiversity and Genetic Resources, Universidade do Porto, Vairão, Distrito do Porto, 4485-661, Portugal
| | - Meritxell Oliva
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - David Castellano
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Lorena Pantano
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Bárbara D Bitarello
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Saxony, 04103, Germany
| | - David Izquierdo
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Isaac Noguera
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Iñigo Olalde
- Institute of Evolutionary Biology, CSIC-Universitat Pompeu Fabra, Barcelona, 08003, Spain
| | - Alejandra Delprat
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Antoine Blancher
- Laboratoire d'immunologie, CHU de Toulouse, IFB Hôpital Purpan, Toulouse, 31059, France.,Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paul Sabatier (UPS), Toulouse, 31024, France
| | - Carles Lalueza-Fox
- Institute of Evolutionary Biology, CSIC-Universitat Pompeu Fabra, Barcelona, 08003, Spain
| | - Tõnu Esko
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia
| | - Paul F O'Reilly
- Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK
| | - Aida M Andrés
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Saxony, 04103, Germany.,UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK
| | - Luca Ferretti
- Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7LF, UK
| | - Marta Puig
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain
| | - Mario Cáceres
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain. .,ICREA, Barcelona, 08010, Spain.
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29
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De Coster W, Van Broeckhoven C. Newest Methods for Detecting Structural Variations. Trends Biotechnol 2019; 37:973-982. [DOI: 10.1016/j.tibtech.2019.02.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 02/08/2019] [Accepted: 02/11/2019] [Indexed: 01/28/2023]
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Assessment of risk factor variants of LRRK2, MAPT, SNCA and TCEANC2 genes in Hungarian sporadic Parkinson's disease patients. Neurosci Lett 2019; 706:140-145. [PMID: 31085292 DOI: 10.1016/j.neulet.2019.05.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 05/09/2019] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Parkinson's disease is the second most common neurodegenerative disease. Lifestyle, environmental effects and several genetic factors have been proposed to contribute to its development. Though the majority of PD cases do not have a family history of disease, genetic alterations are proposed to be present in 60 percent of the more common sporadic cases. OBJECTIVE The aim of this study is to evaluate the frequency of PD related specific risk variants of LRRK2, MAPT, SNCA and PARK10 genes in the Hungarian population. Out of the ten investigated polymorphisms three are proposed to have protective effect and seven are putative risk factors. METHODS For genotyping, TaqMan allelic discrimination and restriction fragment length polymorphism method was used. LRRK2 mutations were investigated among 124 sporadic PD patients and 128 healthy controls. MAPT and SNCA variant frequencies were evaluated in a group of 123 patients and 122 controls, while PARK10 variant was studied in groups of 121 patients and 113 controls. RESULTS No significant difference could be detected in the frequencies of the investigated MAPT and PARK10 variants between the studied Hungarian PD cases and controls. The minor allele of the risk factor S1647T LRRK2 variant was found to be more frequent among healthy male individuals compared to patients. Moreover, in the frequency of one of the investigated SNCA variant a significant intergroup difference was detected. The minor allele (A) of rs356186 is proposed to be protective against developing the disease. In accord with data obtained in other populations, the AA genotype was significantly more frequent among Hungarian healthy controls compared to patients. Similarly, a significant difference in genotype distribution was also found in comparison of patients with late onset disease to healthy controls, which was due to the higher frequency of AG genotype among patients. CONCLUSION The frequencies of different gene variants show great differences in populations. Assessment of the frequency of variants of PD related genes variants is important in order to uncover the pathomechanisms underlying the disease, and to identify potential therapeutic targets. This is the first comprehensive study focusing on these genetic variants in the population of East-Central European region. Our results extend the knowledge on the world wide occurrence of these polymorphisms by demonstrating the occurrence of specific alleles and absence of others in Hungarian PD patients.
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Katzeff JS, Phan K, Purushothuman S, Halliday GM, Kim WS. Cross-examining candidate genes implicated in multiple system atrophy. Acta Neuropathol Commun 2019; 7:117. [PMID: 31340844 PMCID: PMC6651992 DOI: 10.1186/s40478-019-0769-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 07/14/2019] [Indexed: 12/26/2022] Open
Abstract
Multiple system atrophy (MSA) is a devastating neurodegenerative disease characterized by the clinical triad of parkinsonism, cerebellar ataxia and autonomic failure, impacting on striatonigral, olivopontocerebellar and autonomic systems. At early stage of the disease, the clinical symptoms of MSA can overlap with those of Parkinson's disease (PD). The key pathological hallmark of MSA is the presence of glial cytoplasmic inclusions (GCI) in oligodendrocytes. GCI comprise insoluble proteinaceous filaments composed chiefly of α-synuclein aggregates, and therefore MSA is regarded as an α-synucleinopathy along with PD and dementia with Lewy bodies. The etiology of MSA is unknown, and the pathogenesis of MSA is still largely speculative. Much data suggests that MSA is a sporadic disease, although some emerging evidence suggests rare genetic variants increase susceptibility. Currently, there is no general consensus on the susceptibility genes as there have been differences due to geographical distribution or ethnicity. Furthermore, many of the reported studies have been conducted on patients that were only clinically diagnosed without pathological verification. The purpose of this review is to bring together available evidence to cross-examine the susceptibility genes and genetic pathomechanisms implicated in MSA. We explore the possible involvement of the SNCA, COQ2, MAPT, GBA1, LRRK2 and C9orf72 genes in MSA pathogenesis, highlight the under-explored areas of MSA genetics, and discuss future directions of research in MSA.
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Affiliation(s)
- Jared S Katzeff
- Brain and Mind Centre & Central Clinical School, The University of Sydney, Sydney, NSW, Australia
| | - Katherine Phan
- Brain and Mind Centre & Central Clinical School, The University of Sydney, Sydney, NSW, Australia
| | - Sivaraman Purushothuman
- Brain and Mind Centre & Central Clinical School, The University of Sydney, Sydney, NSW, Australia
| | - Glenda M Halliday
- Brain and Mind Centre & Central Clinical School, The University of Sydney, Sydney, NSW, Australia
| | - Woojin Scott Kim
- Brain and Mind Centre & Central Clinical School, The University of Sydney, Sydney, NSW, Australia.
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Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy. J Transl Med 2019; 99:993-1007. [PMID: 30742063 PMCID: PMC6609463 DOI: 10.1038/s41374-019-0196-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/04/2019] [Accepted: 01/07/2019] [Indexed: 12/11/2022] Open
Abstract
We review the literature on Tau and TDP-43 proteinopathies in aged human brains and the relevant underlying pathogenetic cascades. Complex interacting pathways are implicated in Alzheimer's disease and related dementias (ADRD), wherein multiple proteins tend to misfold in a manner that is "reactive," but, subsequently, each proteinopathy may contribute strongly to the clinical symptoms. Tau proteinopathy exists in brains of individuals across a broad spectrum of primary underlying conditions-e.g., developmental, traumatic, and inflammatory/infectious diseases. TDP-43 proteinopathy is also expressed in a wide range of clinical disorders. Although TDP-43 proteinopathy was first described in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) and in subtypes of frontotemporal dementia (FTD/FTLD), TDP-43 proteinopathy is also present in chronic traumatic encephalopathy, cognitively impaired persons in advanced age with hippocampal sclerosis, Huntington's disease, and other diseases. We list known Tau and TDP-43 proteinopathies. There is also evidence of cellular co-localization between Tau and TDP-43 misfolded proteins, suggesting common pathways or protein interactions facilitating misfolding in one protein by the other. Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g., APOE ε4, Huntingtin triplet repeats) are associated with increases of both Tau and TDP-43 proteinopathies. Studies of genetic risk factors have provided insights into multiple nodes of the pathologic cascades involved in Tau and TDP-43 proteinopathies. Variants from a specific gene can be either a low-penetrant risk factor for a group of diseases, or alternatively, a different variant of the same gene may be a disease-driving allele that is associated with a relatively aggressive and early-onset version of a clinically and pathologically specific disease type. Overall, a complex but enlightening paradigm has emerged, wherein both Tau and TDP-43 proteinopathies are linked to numerous overlapping upstream influences, and both are associated with multiple downstream pathologically- and clinically-defined deleterious effects.
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Li YI, Wong G, Humphrey J, Raj T. Prioritizing Parkinson's disease genes using population-scale transcriptomic data. Nat Commun 2019; 10:994. [PMID: 30824768 PMCID: PMC6397174 DOI: 10.1038/s41467-019-08912-9] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 02/05/2019] [Indexed: 12/23/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified over 41 susceptibility loci associated with Parkinson's Disease (PD) but identifying putative causal genes and the underlying mechanisms remains challenging. Here, we leverage large-scale transcriptomic datasets to prioritize genes that are likely to affect PD by using a transcriptome-wide association study (TWAS) approach. Using this approach, we identify 66 gene associations whose predicted expression or splicing levels in dorsolateral prefrontal cortex (DLFPC) and peripheral monocytes are significantly associated with PD risk. We uncover many novel genes associated with PD but also novel mechanisms for known associations such as MAPT, for which we find that variation in exon 3 splicing explains the common genetic association. Genes identified in our analyses belong to the same or related pathways including lysosomal and innate immune function. Overall, our study provides a strong foundation for further mechanistic studies that will elucidate the molecular drivers of PD.
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Affiliation(s)
- Yang I Li
- Section of Genetic Medicine, Department of Medicine, and Department of Human Genetics, University of Chicago, Chicago, 60637, IL, USA
| | - Garrett Wong
- Departments of Neuroscience, and Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Jack Humphrey
- UCL Genetics Institute, Gower Street, London, WC1E 6BT, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1E 6BT, UK
| | - Towfique Raj
- Departments of Neuroscience, and Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
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Cilento EM, Jin L, Stewart T, Shi M, Sheng L, Zhang J. Mass spectrometry: A platform for biomarker discovery and validation for Alzheimer's and Parkinson's diseases. J Neurochem 2019; 151:397-416. [PMID: 30474862 DOI: 10.1111/jnc.14635] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/15/2018] [Accepted: 11/19/2018] [Indexed: 12/16/2022]
Abstract
Accurate, reliable, and objective biomarkers for Alzheimer's disease (AD), Parkinson's disease (PD), and related age-associated neurodegenerative disorders are urgently needed to assist in both diagnosis, particularly at early stages, and monitoring of disease progression. Technological advancements in protein detection platforms over the last few decades have resulted in a plethora of reported molecular biomarker candidates for both AD and PD; however, very few of these candidates are developed beyond the discovery phase of the biomarker development pipeline, a reflection of the current bottleneck within the field. In this review, the expanded use of selected reaction monitoring (SRM) targeted mass spectrometry will be discussed in detail as a platform for systematic verification of large panels of protein biomarker candidates prior to costly validation testing. We also advocate for the coupling of discovery-based proteomics with modern targeted MS-based approaches (e.g., SRM) within a single study in future workflows to expedite biomarker development and validation for AD and PD. It is our hope that improving the efficiency within the biomarker development process by use of an SRM pipeline may ultimately hasten the development of biomarkers that both decrease misdiagnosis of AD and PD and ultimately lead to detection at early stages of disease and objective assessment of disease progression. This article is part of the special issue "Proteomics".
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Affiliation(s)
- Eugene M Cilento
- Department of Pathology, University of Washington, School of Medicine, Seattle, Washington, USA
| | - Lorrain Jin
- Department of Pathology, University of Washington, School of Medicine, Seattle, Washington, USA
| | - Tessandra Stewart
- Department of Pathology, University of Washington, School of Medicine, Seattle, Washington, USA
| | - Min Shi
- Department of Pathology, University of Washington, School of Medicine, Seattle, Washington, USA
| | - Lifu Sheng
- Department of Pathology, University of Washington, School of Medicine, Seattle, Washington, USA
| | - Jing Zhang
- Department of Pathology, University of Washington, School of Medicine, Seattle, Washington, USA.,Department of Pathology, School of Basic Medicine, Peking University Health Science Center, Peking University Third Hospital and Peking Key Laboratory for Early Diagnosis of Neurodegenerative Disorders, Beijing, China
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35
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Shi M, Sheng L, Stewart T, Zabetian CP, Zhang J. New windows into the brain: Central nervous system-derived extracellular vesicles in blood. Prog Neurobiol 2019; 175:96-106. [PMID: 30685501 DOI: 10.1016/j.pneurobio.2019.01.005] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/18/2018] [Accepted: 01/23/2019] [Indexed: 12/28/2022]
Abstract
Extracellular vesicles (EVs), including exosomes and (shedding) microvesicles, are released by nearly all cell types and carry a cargo of proteins and nucleic acids that varies by the cell of origin. They are thought to play critical roles in normal central nervous system (CNS) function and neurological disorders. A recently revealed key characteristic of EVs is that they may travel between the CNS and peripheral circulation. This property has led to intense interest in how EVs might serve as a vehicle for toxic protein clearance and as a readily accessible source of biomarkers for CNS disorders. Furthermore, by bypassing the blood-brain barrier, modified EVs could serve as a unique drug delivery system that targets specific neuronal populations. Further work is necessary to develop and optimize techniques that enable high-yield capture of relevant EV populations, analyze individual EVs and their cargos, and validate preliminary results of EV-derived biomarkers in independent cohorts.
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Affiliation(s)
- Min Shi
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - Lifu Sheng
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - Tessandra Stewart
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - Cyrus P Zabetian
- Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Jing Zhang
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA; Beijing Key Laboratory of Research and Transformation on Neurodegenerative Diseases Biomarkers, Department of Pathology, Peking University Third Hospital/Institute of Basic Science, Peking University Health Science Center, Beijing 100083, China.
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36
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Coughlin D, Xie SX, Liang M, Williams A, Peterson C, Weintraub D, McMillan CT, Wolk DA, Akhtar RS, Hurtig HI, Branch Coslett H, Hamilton RH, Siderowf AD, Duda JE, Rascovsky K, Lee EB, Lee VMY, Grossman M, Trojanowski JQ, Irwin DJ. Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders. Ann Neurol 2019; 85:259-271. [PMID: 30549331 DOI: 10.1002/ana.25392] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 12/04/2018] [Accepted: 12/05/2018] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. METHODS Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. RESULTS SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (F1, 54 = 5.6-6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43-49 = 0.7-1.7, p > 0.2). SYN + AD performed worse than SYN-AD on a temporal lobe-mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = -0.39 to -0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8-97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F1, 40-43 = 1.6-2.0, p > 0.1). INTERPRETATION LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.
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Affiliation(s)
- David Coughlin
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Digital Neuropathology Laboratory, Perelman School of Medicine at the University of Pennsylvania.,Frontotemporal Dementia Center, Perelman School of Medicine at the University of Pennsylvania.,Parkinson's Disease and Movement Disorders Center, Perelman School of Medicine at the University of Pennsylvania
| | - Sharon X Xie
- Alzheimer's Disease Center, Perelman School of Medicine at the University of Pennsylvania.,Department of Biostatistics, Epidemiology and Informatics Perelman School of Medicine at the University of Pennsylvania
| | - Mendy Liang
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Digital Neuropathology Laboratory, Perelman School of Medicine at the University of Pennsylvania
| | - Andrew Williams
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Digital Neuropathology Laboratory, Perelman School of Medicine at the University of Pennsylvania
| | - Claire Peterson
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Digital Neuropathology Laboratory, Perelman School of Medicine at the University of Pennsylvania
| | - Daniel Weintraub
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Parkinson's Disease and Movement Disorders Center, Perelman School of Medicine at the University of Pennsylvania.,Michael J. Crescenz VA Medical Center, Parkinson's Disease Research, Education, and Clinical Center, Philadelphia, PA, USA 19104
| | - Corey T McMillan
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Frontotemporal Dementia Center, Perelman School of Medicine at the University of Pennsylvania
| | - David A Wolk
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Alzheimer's Disease Center, Perelman School of Medicine at the University of Pennsylvania
| | - Rizwan S Akhtar
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Parkinson's Disease and Movement Disorders Center, Perelman School of Medicine at the University of Pennsylvania
| | - Howard I Hurtig
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Parkinson's Disease and Movement Disorders Center, Perelman School of Medicine at the University of Pennsylvania
| | - H Branch Coslett
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Center for Cognitive Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Roy H Hamilton
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Center for Cognitive Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Andrew D Siderowf
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Parkinson's Disease and Movement Disorders Center, Perelman School of Medicine at the University of Pennsylvania
| | - John E Duda
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Michael J. Crescenz VA Medical Center, Parkinson's Disease Research, Education, and Clinical Center, Philadelphia, PA, USA 19104
| | - Katya Rascovsky
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Frontotemporal Dementia Center, Perelman School of Medicine at the University of Pennsylvania
| | - Edward B Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania.,Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania.,Alzheimer's Disease Center, Perelman School of Medicine at the University of Pennsylvania
| | - Virginia M-Y Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania.,Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania.,Alzheimer's Disease Center, Perelman School of Medicine at the University of Pennsylvania
| | - Murray Grossman
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Frontotemporal Dementia Center, Perelman School of Medicine at the University of Pennsylvania
| | - John Q Trojanowski
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania.,Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania.,Alzheimer's Disease Center, Perelman School of Medicine at the University of Pennsylvania
| | - David J Irwin
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania.,Digital Neuropathology Laboratory, Perelman School of Medicine at the University of Pennsylvania.,Frontotemporal Dementia Center, Perelman School of Medicine at the University of Pennsylvania
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37
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Drosophila Models of Sporadic Parkinson's Disease. Int J Mol Sci 2018; 19:ijms19113343. [PMID: 30373150 PMCID: PMC6275057 DOI: 10.3390/ijms19113343] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/22/2018] [Accepted: 10/23/2018] [Indexed: 12/17/2022] Open
Abstract
Parkinson’s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress, aiming to provide mechanistic insights into the pathogenesis of PD. This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophilamelanogaster and discusses their methodologies, new findings, and future perspectives.
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Irwin DJ, Hurtig HI. The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders. JOURNAL OF ALZHEIMER'S DISEASE & PARKINSONISM 2018; 8:444. [PMID: 30473927 PMCID: PMC6248323 DOI: 10.4172/2161-0460.1000444] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Parkinson's Disease (PD) and the closely related Dementia with Lewy Bodies (DLB) are due to the accumulation of pathogenic alpha-synuclein protein in brain cells manifest by heterogeneous motor and non-motor symptoms, including cognitive impairment and dementia. The majority of patients with Parkinson's Disease develop Dementia (PDD) in late stages of the disease and have widespread neocortical distribution of alpha-synuclein pathology at autopsy, compared with PD without dementia, in which neocortical synuclein pathology is less prevalent. These three entities PD, DLB and PDD comprise a clinical spectrum, collectively known as Lewy Body Disorders (LBD). Recent investigations into the neuropathological basis of LBD have demonstrated that while synuclein pathology is the defining feature of these disorders, it is often accompanied by other age-related neurodegenerative pathologies. In particular, amyloid plaque and tau tangle pathology characteristic of Alzheimer's Disease (AD) (~50% of all LBD patients have sufficient pathology at autopsy for a secondary neuropathologic diagnosis of AD), appear to contribute to cognitive impairment in LBD, and the combination is associated with a shorter interval between onset of motor symptoms and development of dementia and a shorter life span. Further, the co-occurrence of neocortical alpha-synuclein, tau and amyloid pathologies found at end-stage disease suggests a potential synergistic interaction of these individual pathologies in humans during life, mirroring experimental observations in animal and cell model systems that show how pathogenic species of synuclein fibrils can promote trans-synaptic spread of both tauopathy and synucleinopathy with strain-like properties. Newer post-mortem studies using digital methods to measure pathologic burden have highlighted distinct neocortical patterns of areas with relative higher density of tau pathology in LBD compared to AD that support these model data. The emerging field of cerebrospinal fluid and molecular imaging biomarkers of synuclein, amyloid and tau pathologies in LBD is contributing to a greater understanding of how the different pathologies evolve and interact to produce clinical heterogeneity in LBD. Future work to elucidate biologically meaningful clinical subgroups of synucleinopathy and its co-pathology must focus on the full clinicopathological spectrum of LBD and use validated biomarkers, when available, to design clinical trials based on the precise selection of homogeneous patient subgroups to maximize statistical power for detecting the impact of treatment.
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Affiliation(s)
- David J. Irwin
- University of Pennsylvania Perelman School of Medicine, Department of Neurology Philadelphia PA, USA
| | - Howard I. Hurtig
- University of Pennsylvania Perelman School of Medicine, Department of Neurology Philadelphia PA, USA
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39
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Li J, Ruskey JA, Arnulf I, Dauvilliers Y, Hu MTM, Högl B, Leblond CS, Zhou S, Ambalavanan A, Ross JP, Bourassa CV, Spiegelman D, Laurent SB, Stefani A, Charley Monaca C, Cochen De Cock V, Boivin M, Ferini-Strambi L, Plazzi G, Antelmi E, Young P, Heidbreder A, Labbe C, Ferman TJ, Dion PA, Fan D, Desautels A, Gagnon JF, Dupré N, Fon EA, Montplaisir JY, Boeve BF, Postuma RB, Rouleau GA, Ross OA, Gan-Or Z. Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder. Mov Disord 2018; 33:1016-1020. [PMID: 29756641 DOI: 10.1002/mds.27385] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 01/29/2018] [Accepted: 02/05/2018] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. OBJECTIVE To study the role of MAPT variants in rapid eye movement sleep behavior disorder. METHODS Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT-associated variants and the entire coding sequence of MAPT were analyzed. Age-, sex-, and ethnicity-adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. RESULTS MAPT-H2 variants were associated with PD (odds ratios: 0.62-0.65; P = 0.010-0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12-2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48-0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. CONCLUSIONS Our results confirm the protective effect of the MAPT-H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Jiao Li
- Department of Neurology, Peking University Third Hospital, Beijing, China.,Montreal Neurological Institute, McGill University, Montréal, QC, Canada
| | - Jennifer A Ruskey
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Isabelle Arnulf
- Sleep Disorders Unit, Pitié Salpêtrière Hospital, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière and Sorbonne Universities, UPMC Paris 6 univ, Paris, France
| | - Yves Dauvilliers
- Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology Hôpital-Gui-de Chauliac, CHU Montpellier, INSERM U1061, Montpellier, France
| | - Michele T M Hu
- Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, United Kingdom.,Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Birgit Högl
- Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Claire S Leblond
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Human Genetics, McGill University, H3A 0G4, Montréal, QC, Canada
| | - Sirui Zhou
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Amirthagowri Ambalavanan
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Jay P Ross
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Human Genetics, McGill University, H3A 0G4, Montréal, QC, Canada
| | - Cynthia V Bourassa
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Dan Spiegelman
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Sandra B Laurent
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Ambra Stefani
- Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christelle Charley Monaca
- University Lille north of France, Department of clinical neurophysiology and sleep center, CHU Lille, Lille, France
| | - Valérie Cochen De Cock
- Sleep and neurology unit, Beau Soleil Clinic, Montpellier, France.,EuroMov, University of Montpellier, Montpellier, France
| | - Michel Boivin
- GRIP, École de psychologie, Université Laval, Québec city, QC, Canada.,Institute of Genetic, Neurobiological and Social Foundations of Child Development, Tomsk State University, Tomsk, Russia
| | - Luigi Ferini-Strambi
- Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy
| | - Giuseppe Plazzi
- Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy.,IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy
| | - Elena Antelmi
- Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy.,IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy
| | - Peter Young
- Department of Sleep Medicine and Neuromuscular Disorders, University of Muenster, Muenster, Germany
| | - Anna Heidbreder
- Department of Sleep Medicine and Neuromuscular Disorders, University of Muenster, Muenster, Germany
| | - Catherine Labbe
- Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, Florida, USA
| | - Tanis J Ferman
- Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, Florida, USA
| | - Patrick A Dion
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Dongsheng Fan
- Department of Neurology, Peking University Third Hospital, Beijing, China
| | - Alex Desautels
- Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada.,Department of Neurosciences, Université de Montréal, Montréal, QC, Canada
| | - Jean-François Gagnon
- Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada.,Département de psychologie, Université du Québec à Montréal, Montréal, QC, Canada
| | - Nicolas Dupré
- Division of Neurosciences, CHU de Québec, Université Laval, Quebec City, QC, Canada.,Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | - Edward A Fon
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada
| | - Jacques Y Montplaisir
- Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, QC, Canada.,Department of Psychiatry, Université de Montréal, Montréal, QC, Canada
| | - Bradley F Boeve
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ronald B Postuma
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.,Department of Neurology, Montreal General Hospital, Montréal, QC, Canada
| | - Guy A Rouleau
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.,Department of Human Genetics, McGill University, H3A 0G4, Montréal, QC, Canada
| | - Owen A Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.,Department of Clinical Genomics, Mayo Clinic, Jacksonville, Florida, USA
| | - Ziv Gan-Or
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada.,Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.,Department of Human Genetics, McGill University, H3A 0G4, Montréal, QC, Canada
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Bonham LW, Karch CM, Fan CC, Tan C, Geier EG, Wang Y, Wen N, Broce IJ, Li Y, Barkovich MJ, Ferrari R, Hardy J, Momeni P, Höglinger G, Müller U, Hess CP, Sugrue LP, Dillon WP, Schellenberg GD, Miller BL, Andreassen OA, Dale AM, Barkovich AJ, Yokoyama JS, Desikan RS. CXCR4 involvement in neurodegenerative diseases. Transl Psychiatry 2018; 8:73. [PMID: 29636460 PMCID: PMC5893558 DOI: 10.1038/s41398-017-0049-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 09/13/2017] [Indexed: 12/14/2022] Open
Abstract
Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.
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Affiliation(s)
- Luke W. Bonham
- 0000 0001 2297 6811grid.266102.1Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA USA
| | - Celeste M. Karch
- 0000 0001 2355 7002grid.4367.6Department of Psychiatry, Washington University, St. Louis, MO USA
| | - Chun C. Fan
- 0000 0001 2107 4242grid.266100.3Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA USA
| | - Chin Tan
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - Ethan G. Geier
- 0000 0001 2297 6811grid.266102.1Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA USA
| | - Yunpeng Wang
- 0000 0004 0389 8485grid.55325.34NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Natalie Wen
- 0000 0001 2355 7002grid.4367.6Department of Psychiatry, Washington University, St. Louis, MO USA
| | - Iris J. Broce
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - Yi Li
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - Matthew J. Barkovich
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - Raffaele Ferrari
- 0000000121901201grid.83440.3bDepartment of Molecular Neuroscience, Institute of Neurology, UCL, London, UK
| | - John Hardy
- 0000000121901201grid.83440.3bDepartment of Molecular Neuroscience, Institute of Neurology, UCL, London, UK
| | - Parastoo Momeni
- 0000 0001 2179 3554grid.416992.1Department of Internal Medicine, Laboratory of Neurogenetics, Texas Tech University Health Science Center, Lubbock, TX USA
| | - Günter Höglinger
- 0000 0004 0438 0426grid.424247.3Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ,0000000123222966grid.6936.aDepartment of Neurology, Technical University of Munich; Munich Cluster for Systems Neurology SyNergy, Munich, Germany
| | - Ulrich Müller
- 0000 0001 2165 8627grid.8664.cInstitut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany
| | - Christopher P. Hess
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - Leo P. Sugrue
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - William P. Dillon
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - Gerard D. Schellenberg
- 0000 0004 1936 8972grid.25879.31Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA
| | - Bruce L. Miller
- 0000 0001 2297 6811grid.266102.1Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA USA
| | - Ole A. Andreassen
- 0000 0004 0389 8485grid.55325.34NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Anders M. Dale
- 0000 0001 2107 4242grid.266100.3Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA USA ,0000 0001 2107 4242grid.266100.3Department of Neurosciences and Radiology, University of California, San Diego, La Jolla, CA USA
| | - A. James Barkovich
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
| | - Jennifer S. Yokoyama
- 0000 0001 2297 6811grid.266102.1Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA USA
| | - Rahul S. Desikan
- 0000 0001 2297 6811grid.266102.1Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA USA
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Zhang CC, Zhu JX, Wan Y, Tan L, Wang HF, Yu JT, Tan L. Meta-analysis of the association between variants in MAPT and neurodegenerative diseases. Oncotarget 2018; 8:44994-45007. [PMID: 28402959 PMCID: PMC5546535 DOI: 10.18632/oncotarget.16690] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/16/2017] [Indexed: 01/11/2023] Open
Abstract
Microtubule-associated protein tau (MAPT) gene is compelling among the susceptibility genes of neurodegenerative diseases which include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Our meta-analysis aimed to find the association between MAPT and the risk of these diseases. Published literatures were retrieved from MEDLINE and other databases, and 82 case-control studies were recruited. Six haplotype tagging single-nucleotide polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9 and rs7521) and haplotypes (H2 and H1c) were significantly associated with the above diseases. The odds ratios (ORs) and 95 % confidence intervals (CIs) were evaluated by comparison in minor and major allele frequency using the R software. This study demonstrated that different variants in MAPT were associated with AD (rs2471738: OR= 1.04, 95%CI = 1.00 - 1.09; H2: OR = 0.94, 95% CI = 0.91 - 0.97), PD (H2: OR = 0.76, 95% CI = 0.74 - 0.79), PSP (rs242557: OR = 1. 96, 95% CI = 1. 71 - 2.25; rs2471738: OR = 1. 85, 95% CI = 1. 48 - 2.31; H2: OR = 0.20, 95% CI = 0.18 - 0.23), CBD (rs242557: OR = 2.51, 95%CI = 1. 66 -3.78; rs2471738: OR = 2.07, 95%CI = 1. 32 -3.23; H2: OR = OR = 0.30, 95% CI = 0.23 - 0.41) and ALS (H2: OR = 0.92, 95% CI = 0.86 - 0.98) instead of FTD (H2: OR = 1.02, 95% CI = 0.78 - 1.32). In conclusion, MAPT is associated with risk of neurodegenerative diseases, suggesting crucial roles of tau in neurodegenerative processes.
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Affiliation(s)
- Cheng-Cheng Zhang
- Department of Neurology, Qingdao Municipal Hospital, Dalian Medical University, PR China
| | - Jun-Xia Zhu
- Clinical Skills Training Center, Qingdao Municipal Hospital, Qingdao University, PR China
| | - Yu Wan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, PR China
| | - Lin Tan
- College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China
| | - Hui-Fu Wang
- Clinical Skills Training Center, Qingdao Municipal Hospital, Qingdao University, PR China
| | - Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, PR China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Dalian Medical University, PR China.,Department of Neurology, Qingdao Municipal Hospital, Qingdao University, PR China.,College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China
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Ryskalin L, Busceti CL, Limanaqi F, Biagioni F, Gambardella S, Fornai F. A Focus on the Beneficial Effects of Alpha Synuclein and a Re-Appraisal of Synucleinopathies. Curr Protein Pept Sci 2018; 19:598-611. [PMID: 29150919 PMCID: PMC5925871 DOI: 10.2174/1389203718666171117110028] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 11/03/2017] [Accepted: 11/13/2017] [Indexed: 01/01/2023]
Abstract
Alpha synuclein (α-syn) belongs to a class of proteins which are commonly considered to play a detrimental role in neuronal survival. This assumption is based on the occurrence of a severe neuronal degeneration in patients carrying a multiplication of the α-syn gene (SNCA) and in a variety of experimental models, where overexpression of α-syn leads to cell death and neurological impairment. In these conditions, a higher amount of normally structured α-syn produces a damage, which is even worse compared with that produced by α-syn owning an abnormal structure (as occurring following point gene mutations). In line with this, knocking out the expression of α-syn is reported to protect from specific neurotoxins such as 1-methyl, 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the present review we briefly discuss these well-known detrimental effects but we focus on findings showing that, in specific conditions α-syn is beneficial for cell survival. This occurs during methamphetamine intoxication which is counteracted by endogenous α-syn. Similarly, the dysfunction of the chaperone cysteine-string protein- alpha leads to cell pathology which is counteracted by over-expressing α-syn. In line with this, an increased expression of α-syn protects against oxidative damage produced by dopamine. Remarkably, when the lack of α-syn is combined with a depletion of β- and γ- synucleins, alterations in brain structure and function occur. This review tries to balance the evidence showing a beneficial effect with the bulk of data reporting a detrimental effect of endogenous α-syn. The specific role of α-syn as a chaperone protein is discussed to explain such a dual effect.
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Affiliation(s)
- Larisa Ryskalin
- Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126Pisa, Italy
| | - Carla L. Busceti
- I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Isernia, Italy
| | - Fiona Limanaqi
- Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126Pisa, Italy
| | | | | | - Francesco Fornai
- Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126Pisa, Italy
- I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Isernia, Italy
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Genetic risk factors in Finnish patients with Parkinson's disease. Parkinsonism Relat Disord 2017; 45:39-43. [PMID: 29029963 DOI: 10.1016/j.parkreldis.2017.09.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/30/2017] [Accepted: 09/28/2017] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. METHODS The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). RESULTS We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. CONCLUSIONS The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.
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Miranda-Morales E, Meier K, Sandoval-Carrillo A, Salas-Pacheco J, Vázquez-Cárdenas P, Arias-Carrión O. Implications of DNA Methylation in Parkinson's Disease. Front Mol Neurosci 2017; 10:225. [PMID: 28769760 PMCID: PMC5513956 DOI: 10.3389/fnmol.2017.00225] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 07/03/2017] [Indexed: 12/13/2022] Open
Abstract
It has been 200 years since Parkinson’s disease (PD) was first described, yet many aspects of its etiopathogenesis remain unclear. PD is a progressive and complex neurodegenerative disorder caused by genetic and environmental factors including aging, nutrition, pesticides and exposure to heavy metals. DNA methylation may be altered in response to some of these factors; therefore, it is proposed that epigenetic mechanisms, particularly DNA methylation, can have a fundamental role in gene–environment interactions that are related with PD. Epigenetic changes in PD-associated genes are now widely studied in different populations, to discover the mechanisms that contribute to disease development and identify novel biomarkers for early diagnosis and future pharmacological treatment. While initial studies sought to find associations between promoter DNA methylation and the regulation of associated genes in PD brain tissue, more recent studies have described concordant DNA methylation patterns between blood and brain tissue DNA. These data justify the use of peripheral blood samples instead of brain tissue for epigenetic studies. Here, we summarize the current data about DNA methylation changes in PD and discuss the potential of DNA methylation as a potential biomarker for PD. Additionally, we discuss environmental and nutritional factors that have been implicated in DNA methylation. Although the search for significant DNA methylation changes and gene expression analyses of PD-associated genes have yielded inconsistent and contradictory results, epigenetic modifications remain under investigation for their potential to reveal the link between environmental risk factors and the development of PD.
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Affiliation(s)
- Ernesto Miranda-Morales
- Unidad de Trastornos del Movimiento y Sueño, Hospital General Dr. Manuel Gea GonzálezMexico City, Mexico.,Instituto de Investigación Científica, Universidad Juárez del Estado de DurangoDurango, Mexico
| | - Karin Meier
- Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de MéxicoMexico City, Mexico
| | - Ada Sandoval-Carrillo
- Instituto de Investigación Científica, Universidad Juárez del Estado de DurangoDurango, Mexico
| | - José Salas-Pacheco
- Instituto de Investigación Científica, Universidad Juárez del Estado de DurangoDurango, Mexico
| | | | - Oscar Arias-Carrión
- Unidad de Trastornos del Movimiento y Sueño, Hospital General Dr. Manuel Gea GonzálezMexico City, Mexico
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Colom-Cadena M, Grau-Rivera O, Planellas L, Cerquera C, Morenas E, Helgueta S, Muñoz L, Kulisevsky J, Martí MJ, Tolosa E, Clarimon J, Lleó A, Gelpi E. Regional Overlap of Pathologies in Lewy Body Disorders. J Neuropathol Exp Neurol 2017; 76:216-224. [PMID: 28395086 DOI: 10.1093/jnen/nlx002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, β-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, β-amyloid (Aβ), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease [PD], 28 with dementia, and 19 with dementia with Lewy bodies). APOE and MAPT genetic variants were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology. Pathological stages of tau, β-amyloid and α-synuclein pathologies were increased in cases with dementia. Aβ score was the best correlate of the time to dementia in PD. In addition, β-amyloid deposition correlated with α-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD that may have an impact on the clinical expression of the diseases.
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Affiliation(s)
- Martí Colom-Cadena
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
| | - Oriol Grau-Rivera
- Neurological Tissue Bank, Biobanc Hospital Clínic-IDIBAPS, Barcelona, Spain
| | - Lluís Planellas
- Parkinson's Disease and Movement Disorders Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Catalina Cerquera
- Parkinson's Disease and Movement Disorders Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.,Neurology Unit, Hospital Universitario San Ignacio, School of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Estrella Morenas
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
| | - Sergio Helgueta
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
| | - Laia Muñoz
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
| | - Jaime Kulisevsky
- CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
| | - Maria Jose Martí
- CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain.,Parkinson's Disease and Movement Disorders Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Eduard Tolosa
- CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain.,Neurological Tissue Bank, Biobanc Hospital Clínic-IDIBAPS, Barcelona, Spain
| | - Jordi Clarimon
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
| | - Alberto Lleó
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
| | - Ellen Gelpi
- Neurological Tissue Bank, Biobanc Hospital Clínic-IDIBAPS, Barcelona, Spain
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Monfrini E, Di Fonzo A. Leucine-Rich Repeat Kinase (LRRK2) Genetics and Parkinson's Disease. ADVANCES IN NEUROBIOLOGY 2017; 14:3-30. [PMID: 28353276 DOI: 10.1007/978-3-319-49969-7_1] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The discovery of LRRK2 mutations as a cause of Parkinson's disease (PD), including the sporadic late-onset form, established the decisive role of genetics in the field of PD research. Among LRRK2 mutations, the G2019S, mostly lying in a haplotype originating from a common Middle Eastern ancestor, has been identified in different populations worldwide. The G2385R and R1628P variants represent validated risk factors for PD in Asian populations. Here, we describe in detail the origin, the present worldwide epidemiology, and the penetrance of LRRK2 mutations. Furthermore, this chapter aims to characterize other definitely/probably pathogenic mutations and risk variants of LRRK2. Finally, we provide some general guidelines for a LRRK2 genetic testing and counseling. In summary, LRRK2 discovery revolutionized the understanding of PD etiology and laid the foundation for a promising future of genetics in PD research.
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Affiliation(s)
- Edoardo Monfrini
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Alessio Di Fonzo
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
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Back to the tubule: microtubule dynamics in Parkinson's disease. Cell Mol Life Sci 2016; 74:409-434. [PMID: 27600680 PMCID: PMC5241350 DOI: 10.1007/s00018-016-2351-6] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 08/18/2016] [Accepted: 08/29/2016] [Indexed: 12/12/2022]
Abstract
Cytoskeletal homeostasis is essential for the development, survival and maintenance of an efficient nervous system. Microtubules are highly dynamic polymers important for neuronal growth, morphology, migration and polarity. In cooperation with several classes of binding proteins, microtubules regulate long-distance intracellular cargo trafficking along axons and dendrites. The importance of a delicate interplay between cytoskeletal components is reflected in several human neurodegenerative disorders linked to abnormal microtubule dynamics, including Parkinson’s disease (PD). Mounting evidence now suggests PD pathogenesis might be underlined by early cytoskeletal dysfunction. Advances in genetics have identified PD-associated mutations and variants in genes encoding various proteins affecting microtubule function including the microtubule-associated protein tau. In this review, we highlight the role of microtubules, their major posttranslational modifications and microtubule associated proteins in neuronal function. We then present key evidence on the contribution of microtubule dysfunction to PD. Finally, we discuss how regulation of microtubule dynamics with microtubule-targeting agents and deacetylase inhibitors represents a promising strategy for innovative therapeutic development.
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Valenca GT, Srivastava GP, Oliveira-Filho J, White CC, Yu L, Schneider JA, Buchman AS, Shulman JM, Bennett DA, De Jager PL. The Role of MAPT Haplotype H2 and Isoform 1N/4R in Parkinsonism of Older Adults. PLoS One 2016; 11:e0157452. [PMID: 27458716 PMCID: PMC4961370 DOI: 10.1371/journal.pone.0157452] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/31/2016] [Indexed: 01/06/2023] Open
Abstract
Background and Objective Recently, we have shown that the Parkinson’s disease (PD) susceptibility locus MAPT (microtubule associated protein tau) is associated with parkinsonism in older adults without a clinical diagnosis of PD. In this study, we investigated the relationship between parkinsonian signs and MAPT transcripts by assessing the effect of MAPT haplotypes on alternative splicing and expression levels of the most common isoforms in two prospective clinicopathologic studies of aging. Materials and Methods using regression analysis, controlling for age, sex, study and neuropathology, we evaluated 976 subjects with clinical, genotyping and brain pathology data for haplotype analysis. For transcript analysis, we obtained MAPT gene and isoform-level expression from the dorsolateral prefrontal cortex for 505 of these subjects. Results The MAPT H2 haplotype was associated with lower total MAPT expression (p = 1.2x10-14) and global parkinsonism at both study entry (p = 0.001) and proximate to death (p = 0.050). Specifically, haplotype H2 was primarily associated with bradykinesia in both assessments (p<0.001 and p = 0.008). MAPT total expression was associated with age and decreases linearly with advancing age (p<0.001). Analysing MAPT alternative splicing, the expression of 1N/4R isoform was inversely associated with global parkinsonism (p = 0.008) and bradykinesia (p = 0.008). Diminished 1N/4R isoform expression was also associated with H2 (p = 0.001). Conclusions Overall, our results suggest that age and H2 are associated with higher parkinsonism score and decreased total MAPT RNA expression. Additionally, we found that H2 and parkinsonism are associated with altered expression levels of specific isoforms. These findings may contribute to the understanding of the association between MAPT locus and parkinsonism in elderly subjects and in some extent to age-related neurodegenerative diseases.
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Affiliation(s)
- Guilherme T. Valenca
- Movement Disorders Clinic, Roberto Santos General Hospital, Salvador, BA, Brazil
- Health Sciences Center, Federal University of Reconcavo of Bahia, Santo Antonio de Jesus, BA, Brazil
- Post-Graduate Program in Health Sciences, Federal University of Bahia, Salvador, BA, Brazil
- Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America
| | - Gyan P. Srivastava
- Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America
| | - Jamary Oliveira-Filho
- Post-Graduate Program in Health Sciences, Federal University of Bahia, Salvador, BA, Brazil
| | - Charles C. White
- Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America
| | - Lei Yu
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Julie A. Schneider
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Aron S. Buchman
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Joshua M. Shulman
- Departments of Neurology, Molecular and Human Genetics, and Neuroscience, and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, United States of America
| | - David A. Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Philip L. De Jager
- Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America
- * E-mail:
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Pascale E, Di Battista ME, Rubino A, Purcaro C, Valente M, Fattapposta F, Ferraguti G, Meco G. Genetic Architecture of MAPT Gene Region in Parkinson Disease Subtypes. Front Cell Neurosci 2016; 10:96. [PMID: 27147968 PMCID: PMC4826864 DOI: 10.3389/fncel.2016.00096] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 03/29/2016] [Indexed: 01/30/2023] Open
Abstract
The microtubule-associated protein tau (MAPT) region has been conceptualized as a model of the interaction between genetics and functional disease outcomes in neurodegenerative disorders, such as Parkinson disease (PD). Indeed, haplotype-specific differences in expression and alternative splicing of MAPT transcripts affect cellular functions at different levels, increasing susceptibility to a range of neurodegenerative processes. In order to evaluate a possible link between MAPT variants, PD risk and PD motor phenotype, we analyzed the genetic architecture of MAPT in a cohort of PD patients. We observed a statistically significant association between the H1 haplotype and PD risk (79.5 vs 69.5%; χ2 = 9.9; OR, 1.7; 95% CI, 1.2–2.4; p = 0.002). The effect was more evident in non tremor dominant (TD) PD subjects (NTD-PD) (82 vs 69.5%; χ2 = 13.6; OR, 2.03; 95% CI, 1.4–3; p = 0.0003), while no difference emerged between PD subgroup of tremor dominant patients (TD-PD) and control subjects. Examination of specific intra-H1 variations showed that the H1h subhaplotype was overrepresented in NTD-PD patients compared with controls (p = 0.007; OR, 2.9; 95% CI, 1.3–6.3). Although we cannot exclude that MAPT variation may be associated with ethnicity, our results may support the hypothesis that MAPT H1 clade and a specific H1 subhaplotype influence the risk of PD and modulate the clinical expression of the disease, including motor phenotype.
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Affiliation(s)
- Esterina Pascale
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University Rome, Italy
| | - Maria Elena Di Battista
- Department of Neurology and Psychiatry (Parkinson's Centre), Sapienza UniversityRome, Italy; Research Centre of Social Diseases (CIMS), Sapienza UniversityRome, Italy
| | - Alfonso Rubino
- Department of Neurology and Psychiatry (Parkinson's Centre), Sapienza UniversityRome, Italy; Research Centre of Social Diseases (CIMS), Sapienza UniversityRome, Italy
| | - Carlo Purcaro
- Department of Neurology and Psychiatry (Parkinson's Centre), Sapienza UniversityRome, Italy; Research Centre of Social Diseases (CIMS), Sapienza UniversityRome, Italy
| | - Marcella Valente
- Department of Neurology and Psychiatry (Parkinson's Centre), Sapienza UniversityRome, Italy; Research Centre of Social Diseases (CIMS), Sapienza UniversityRome, Italy
| | - Francesco Fattapposta
- Department of Neurology and Psychiatry (Parkinson's Centre), Sapienza University Rome, Italy
| | - Giampiero Ferraguti
- Department of Cellular Biotechnologies and Hematology, Sapienza University Rome, Italy
| | - Giuseppe Meco
- Department of Neurology and Psychiatry (Parkinson's Centre), Sapienza UniversityRome, Italy; Research Centre of Social Diseases (CIMS), Sapienza UniversityRome, Italy
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50
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Paul KC, Rausch R, Creek MM, Sinsheimer JS, Bronstein JM, Bordelon Y, Ritz B. APOE, MAPT, and COMT and Parkinson's Disease Susceptibility and Cognitive Symptom Progression. JOURNAL OF PARKINSON'S DISEASE 2016; 6:349-59. [PMID: 27061069 PMCID: PMC5927361 DOI: 10.3233/jpd-150762] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Cognitive decline is well recognized in Parkinson's disease (PD) and a major concern for patients and caregivers. Apolipoprotein E (APOE), catechol-O-methyl transferase (COMT), and microtubule-associated protein tau (MAPT) are of interest related to their contributions to cognitive decline or dementia in PD. OBJECTIVE Here, we investigate whether APOE, COMT, or MAPT influence the rate of cognitive decline in PD patients. METHODS We relied on 634 PD patients and 879 controls to examine gene-PD susceptibility associations, and nested longitudinal cohort of 246 patients from the case-control study, which followed patients on average 5 years and 7.5 years into disease. We repeatedly assessed cognitive symptom progression with the MMSE and conducted a full neuropsychological battery on a subset of 183 cognitively normal patients. We used repeated-measures regression analyses to assess longitudinal associations between genotypes and cognitive progression scores. RESULTS The MAPT H1 haplotype was associated with PD susceptibility. APOE 4 carriers (ɛ4+) (p = 0.03) and possibly COMT Met/Met (p = 0.06) carriers exhibited faster annual decline on the MMSE. Additionally, APOEɛ4+ carriers showed faster decline in many of the neuropsychological test scores. No such differences in neuropsychological outcomes were seen for the COMT genotypes. CONCLUSION This work supports a growing set of research identifying overlapping etiology and pathology between synucleinopathies, such as PD, Alzheimer's disease, and tauopathies, especially in the context of cognitive dysfunction in PD. We provide support for the argument that APOE ɛ4+ and COMT Met/Met genotypes can be used as predictors of faster cognitive decline in PD.
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Affiliation(s)
- Kimberly C Paul
- Department of Epidemiology, UCLA Fielding School of Public Health,
Los Angeles, California, USA
| | - Rebecca Rausch
- Department of Neurology, David Geffen School of Medicine, Los
Angeles, California, USA
| | - Michelle M Creek
- Department of Biostatistics, UCLA Fielding School of Public Health,
Los Angeles, California, USA
| | - Janet S Sinsheimer
- Department of Biostatistics, UCLA Fielding School of Public Health,
Los Angeles, California, USA
- Department of Human Genetics, David Geffen School of Medicine, Los
Angeles, California, USA
| | - Jeff M Bronstein
- Department of Neurology, David Geffen School of Medicine, Los
Angeles, California, USA
| | - Yvette Bordelon
- Department of Neurology, David Geffen School of Medicine, Los
Angeles, California, USA
| | - Beate Ritz
- Department of Epidemiology, UCLA Fielding School of Public Health,
Los Angeles, California, USA
- Department of Neurology, David Geffen School of Medicine, Los
Angeles, California, USA
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