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Key J, Almaguer-Mederos LE, Kandi AR, Sen NE, Gispert S, Köpf G, Meierhofer D, Auburger G. ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation. Neurobiol Dis 2025; 209:106903. [PMID: 40220918 DOI: 10.1016/j.nbd.2025.106903] [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: 02/27/2025] [Revised: 04/04/2025] [Accepted: 04/04/2025] [Indexed: 04/14/2025] Open
Abstract
The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.
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Affiliation(s)
- Jana Key
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Luis-Enrique Almaguer-Mederos
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Arvind Reddy Kandi
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Nesli-Ece Sen
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Suzana Gispert
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Gabriele Köpf
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
| | - Georg Auburger
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany; Institute for Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Fachbereich Medizin, Goethe University Frankfurt, Frankfurt am Main, Germany.
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2
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Pulst SM. Spinocerebellar Ataxia Type 2: A Review and Personal Perspective. Neurol Genet 2025; 11:e200225. [PMID: 39872677 PMCID: PMC11772019 DOI: 10.1212/nxg.0000000000200225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 10/25/2024] [Indexed: 01/30/2025]
Abstract
Spinocerebellar ataxias (SCAs) are dominantly inherited diseases that lead to neurodegeneration in the cerebellum and other parts of the nervous system. This review examines the progress that has been made in SCA2 from its initial clinical description to discovery of DNA CAG-repeat expansions in the ATXN2 gene. ATXN2 repeat alleles cover the range from recessive and dominant mendelian alleles to risk alleles for amyotrophic lateral sclerosis. We review studies aimed at defining the normal function of ATXN2 and mutant ATXN2 using cellular and mouse models. Progress in testing small compounds and antisense oligonucleotides in preclinical studies is described as well including our recent focus on staufen-1 (STAU1) and mRNA metabolism and control of autophagy.
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Song Rong S, Larson A, Wiggs JL. ATXN2 loss of function results in glaucoma-related features supporting a role for Ataxin-2 in primary open-angle glaucoma (POAG) pathogenesis. Vision Res 2025; 226:108508. [PMID: 39488861 DOI: 10.1016/j.visres.2024.108508] [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: 06/01/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 11/05/2024]
Abstract
Glaucoma is a leading cause of irreversible blindness worldwide. The most common form, primary open-angle glaucoma (POAG), is a genetically complex trait with high heritability. Genome-wide association studies have identified significant POAG and IOP association of a genomic region on chromosome 12 that includes ATXN2 as well as 7 other genes. Association of protein disrupting ATXN2 variants in the NEIGHBORHOOD case-control cohort and the UK Biobank suggests that ATXN2 is a key gene in this locus. To investigate functional effects, we utilized a zebrafish (Danio rerio) CRISPR/Cas9 edited atxn2-knockdown line to show that loss of atxn2 results in reduced eye size, diminished retinal ganglion cells (RGC), increased intraocular pressure (IOP), and impaired visual function in zebrafish. Complementation assays supported functional effects for 14 POAG-associated human ATXN2 missense variants. These results suggest a loss-of-function mechanism underlying a potential role for ATXN2 in POAG pathogenesis.
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Affiliation(s)
- Shi Song Rong
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA
| | - Anna Larson
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA
| | - Janey L Wiggs
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA.
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4
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Ito D, Okada K. Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis. Ann Clin Transl Neurol 2024; 11:3054-3063. [PMID: 39473221 DOI: 10.1002/acn3.52234] [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: 09/16/2024] [Revised: 10/08/2024] [Accepted: 10/09/2024] [Indexed: 12/18/2024] Open
Abstract
Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.
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Affiliation(s)
- Daisuke Ito
- Memory Center, Keio University School of Medicine, Tokyo, Japan
- Department of Neurology, Keio University School of Medicine, Tokyo, Japan
| | - Kensuke Okada
- Department of Neurology, Keio University School of Medicine, Tokyo, Japan
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5
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Vieira de Sá R, Sudria-Lopez E, Cañizares Luna M, Harschnitz O, van den Heuvel DMA, Kling S, Vonk D, Westeneng HJ, Karst H, Bloemenkamp L, Varderidou-Minasian S, Schlegel DK, Mars M, Broekhoven MH, van Kronenburg NCH, Adolfs Y, Vangoor VR, de Jongh R, Ljubikj T, Peeters L, Seeler S, Mocholi E, Basak O, Gordon D, Giuliani F, Verhoeff T, Korsten G, Calafat Pla T, Venø MT, Kjems J, Talbot K, van Es MA, Veldink JH, van den Berg LH, Zelina P, Pasterkamp RJ. ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes. Nat Commun 2024; 15:7484. [PMID: 39209824 PMCID: PMC11362472 DOI: 10.1038/s41467-024-51676-0] [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: 02/24/2023] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43Tg-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.
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Affiliation(s)
- Renata Vieira de Sá
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Emma Sudria-Lopez
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Marta Cañizares Luna
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Oliver Harschnitz
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
- Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX, Utrecht, The Netherlands
- Human Technopole, Viale Rita Levi-Montalcini, 1, 20157, Milan, Italy
| | - Dianne M A van den Heuvel
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Sandra Kling
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Danielle Vonk
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Henk-Jan Westeneng
- Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX, Utrecht, The Netherlands
| | - Henk Karst
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Lauri Bloemenkamp
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Suzy Varderidou-Minasian
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Domino K Schlegel
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Mayte Mars
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Mark H Broekhoven
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Nicky C H van Kronenburg
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Youri Adolfs
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Vamshidhar R Vangoor
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Rianne de Jongh
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Tijana Ljubikj
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Lianne Peeters
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Sabine Seeler
- Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Enric Mocholi
- Center for Molecuar Medicine, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Onur Basak
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - David Gordon
- Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK
| | - Fabrizio Giuliani
- Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX, Utrecht, The Netherlands
| | - Tessa Verhoeff
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Giel Korsten
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Teresa Calafat Pla
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Morten T Venø
- Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Omiics ApS, Aarhus, Denmark
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Kevin Talbot
- Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK
- Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, UK
| | - Michael A van Es
- Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX, Utrecht, The Netherlands
| | - Jan H Veldink
- Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX, Utrecht, The Netherlands
| | - Leonard H van den Berg
- Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX, Utrecht, The Netherlands
| | - Pavol Zelina
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands.
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6
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Li L, Wang M, Huang L, Zheng X, Wang L, Miao H. Ataxin-2: a powerful RNA-binding protein. Discov Oncol 2024; 15:298. [PMID: 39039334 PMCID: PMC11263328 DOI: 10.1007/s12672-024-01158-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 07/15/2024] [Indexed: 07/24/2024] Open
Abstract
Ataxin-2 (ATXN2) was originally discovered in the context of spinocerebellar ataxia type 2 (SCA2), but it has become a key player in various neurodegenerative diseases. This review delves into the multifaceted roles of ATXN2 in human diseases, revealing its diverse molecular and cellular pathways. The impact of ATXN2 on diseases extends beyond functional outcomes; it mainly interacts with various RNA-binding proteins (RBPs) to regulate different stages of post-transcriptional gene expression in diseases. With the progress of research, ATXN2 has also been found to play an important role in the development of various cancers, including breast cancer, gastric cancer, pancreatic cancer, colon cancer, and esophageal cancer. This comprehensive exploration underscores the crucial role of ATXN2 in the pathogenesis of diseases and warrants further investigation by the scientific community. By reviewing the latest discoveries on the regulatory functions of ATXN2 in diseases, this article helps us understand the complex molecular mechanisms of a series of human diseases related to this intriguing protein.
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Affiliation(s)
- Lulu Li
- School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China
- Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University, Chongqing, 400038, China
| | - Meng Wang
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China
| | - Lai Huang
- Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University, Chongqing, 400038, China
| | - Xiaoli Zheng
- School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China.
| | - Lina Wang
- Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University, Chongqing, 400038, China.
| | - Hongming Miao
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China.
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7
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Costa RG, Conceição A, Matos CA, Nóbrega C. The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease. Cell Death Dis 2024; 15:415. [PMID: 38877004 PMCID: PMC11178924 DOI: 10.1038/s41419-024-06812-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 06/16/2024]
Abstract
A CAG repeat sequence in the ATXN2 gene encodes a polyglutamine (polyQ) tract within the ataxin-2 (ATXN2) protein, showcasing a complex landscape of functions that have been progressively unveiled over recent decades. Despite significant progresses in the field, a comprehensive overview of the mechanisms governed by ATXN2 remains elusive. This multifaceted protein emerges as a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm. The CAG overexpansion within the ATXN2 gene produces a protein with an extended poly(Q) tract, inducing consequential alterations in conformational dynamics which confer a toxic gain and/or partial loss of function. Although overexpanded ATXN2 is predominantly linked to spinocerebellar ataxia type 2 (SCA2), intermediate expansions are also implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism. While the molecular intricacies await full elucidation, SCA2 presents ATXN2-associated pathological features, encompassing autophagy impairment, RNA-mediated toxicity, heightened oxidative stress, and disruption of calcium homeostasis. Presently, SCA2 remains incurable, with patients reliant on symptomatic and supportive treatments. In the pursuit of therapeutic solutions, various studies have explored avenues ranging from pharmacological drugs to advanced therapies, including cell or gene-based approaches. These endeavours aim to address the root causes or counteract distinct pathological features of SCA2. This review is intended to provide an updated compendium of ATXN2 functions, delineate the associated pathological mechanisms, and present current perspectives on the development of innovative therapeutic strategies.
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Affiliation(s)
- Rafael G Costa
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal.
- PhD program in Biomedical Sciences, Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve (UAlg), Faro, Portugal.
- Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve (UAlg), Faro, Portugal.
| | - André Conceição
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
- PhD program in Biomedical Sciences, Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve (UAlg), Faro, Portugal
- Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve (UAlg), Faro, Portugal
- Center for Neuroscience and Cell Biology (CNC), Coimbra, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, Lisbon, Portugal
| | - Carlos A Matos
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal
- Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve (UAlg), Faro, Portugal
| | - Clévio Nóbrega
- Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal.
- Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve (UAlg), Faro, Portugal.
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Perlegos AE, Durkin J, Belfer SJ, Rodriguez A, Shcherbakova O, Park K, Luong J, Bonini NM, Kayser MS. TDP-43 impairs sleep in Drosophila through Ataxin-2-dependent metabolic disturbance. SCIENCE ADVANCES 2024; 10:eadj4457. [PMID: 38198547 PMCID: PMC10780954 DOI: 10.1126/sciadv.adj4457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024]
Abstract
Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila. Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2-regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.
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Affiliation(s)
- Alexandra E. Perlegos
- Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jaclyn Durkin
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- National Institute of Neurological Disorders & Stroke, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Samuel J. Belfer
- Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anyara Rodriguez
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Oksana Shcherbakova
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kristen Park
- Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jenny Luong
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nancy M. Bonini
- Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthew S. Kayser
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Chronobiology Sleep Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
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9
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Felício D, du Mérac TR, Amorim A, Martins S. Functional implications of paralog genes in polyglutamine spinocerebellar ataxias. Hum Genet 2023; 142:1651-1676. [PMID: 37845370 PMCID: PMC10676324 DOI: 10.1007/s00439-023-02607-4] [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: 07/10/2023] [Accepted: 09/22/2023] [Indexed: 10/18/2023]
Abstract
Polyglutamine (polyQ) spinocerebellar ataxias (SCAs) comprise a group of autosomal dominant neurodegenerative disorders caused by (CAG/CAA)n expansions. The elongated stretches of adjacent glutamines alter the conformation of the native proteins inducing neurotoxicity, and subsequent motor and neurological symptoms. Although the etiology and neuropathology of most polyQ SCAs have been extensively studied, only a limited selection of therapies is available. Previous studies on SCA1 demonstrated that ATXN1L, a human duplicated gene of the disease-associated ATXN1, alleviated neuropathology in mice models. Other SCA-associated genes have paralogs (i.e., copies at different chromosomal locations derived from duplication of the parental gene), but their functional relevance and potential role in disease pathogenesis remain unexplored. Here, we review the protein homology, expression pattern, and molecular functions of paralogs in seven polyQ dominant ataxias-SCA1, SCA2, MJD/SCA3, SCA6, SCA7, SCA17, and DRPLA. Besides ATXN1L, we highlight ATXN2L, ATXN3L, CACNA1B, ATXN7L1, ATXN7L2, TBPL2, and RERE as promising functional candidates to play a role in the neuropathology of the respective SCA, along with the parental gene. Although most of these duplicates lack the (CAG/CAA)n region, if functionally redundant, they may compensate for a partial loss-of-function or dysfunction of the wild-type genes in SCAs. We aim to draw attention to the hypothesis that paralogs of disease-associated genes may underlie the complex neuropathology of dominant ataxias and potentiate new therapeutic strategies.
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Affiliation(s)
- Daniela Felício
- Instituto de Investigação e Inovação em Saúde (i3S), 4200-135, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135, Porto, Portugal
- Instituto Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313, Porto, Portugal
| | - Tanguy Rubat du Mérac
- Instituto de Investigação e Inovação em Saúde (i3S), 4200-135, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135, Porto, Portugal
- Faculty of Science, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands
| | - António Amorim
- Instituto de Investigação e Inovação em Saúde (i3S), 4200-135, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135, Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, 4169-007, Porto, Portugal
| | - Sandra Martins
- Instituto de Investigação e Inovação em Saúde (i3S), 4200-135, Porto, Portugal.
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135, Porto, Portugal.
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10
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Zhang W, Zhang L, Zhu J, Xiao C, Cui H, Yang C, Yan P, Tang M, Wang Y, Chen L, Liu Y, Zou Y, Wu X, Zhang L, Yang C, Yao Y, Li J, Liu Z, Jiang X, Zhang B. Additional Evidence for the Relationship Between Type 2 Diabetes and Stroke Through Observational and Genetic Analyses. Diabetes 2023; 72:1671-1681. [PMID: 37552871 DOI: 10.2337/db22-0954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 08/01/2023] [Indexed: 08/10/2023]
Abstract
While type 2 diabetes mellitus (T2DM) is commonly considered a putative causal risk factor for stroke, the effect of stroke on T2DM remains unclear. The intrinsic link underlying T2DM and stroke has not been thoroughly examined. We aimed to evaluate the phenotypic and genetic relationships underlying T2DM and stroke. We evaluated phenotypic associations using data from the UK Biobank (N = 472,050). We then investigated genetic relationships by leveraging genomic data in European ancestry for T2DM, with and without adjusting (adj) for BMI (T2DM: n = 74,124 case subjects/824,006 control subjects; T2DMadjBMI: n = 50,409 case subjects/523,897 control subjects), and for stroke (n = 73,652 case subjects/1,234,808 control subjects). We performed additional analyses using genomic data in East Asian ancestry for T2DM (n = 77,418 case subjects/356,122 control subjects) and for stroke (n = 27,413 case subjects/237,242 control subjects). Observational analyses suggested a significantly increased hazard of stroke among individuals with T2DM (hazard ratio 2.28 [95% CI 1.97-2.64]), but a slightly increased hazard of T2DM among individuals with stroke (1.22 [1.03-1.45]) which attenuated to 1.14 (0.96-1.36) in sensitivity analysis. A positive global T2DM-stroke genetic correlation was observed (rg = 0.35; P = 1.46 × 10-27), largely independent of BMI (T2DMadjBMI-stroke: rg = 0.27; P = 3.59 × 10-13). This was further corroborated by 38 shared independent loci and 161 shared expression-trait associations. Mendelian randomization analyses suggested a putative causal effect of T2DM on stroke in Europeans (odds ratio 1.07 [95% CI 1.06-1.09]), which remained significant in East Asians (1.03 [1.01-1.06]). Conversely, despite a putative causal effect of stroke on T2DM also observed in Europeans (1.21 [1.07-1.37]), it attenuated to 1.04 (0.91-1.19) in East Asians. Our study provides additional evidence to underscore the significant relationship between T2DM and stroke. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Wenqiang Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Li Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Jingwei Zhu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Chenghan Xiao
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
- Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Huijie Cui
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Chao Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Peijing Yan
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Mingshuang Tang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Yutong Wang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Lin Chen
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Yunjie Liu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Yanqiu Zou
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Xueyao Wu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Ling Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
- Department of Iatrical Polymer Material and Artificial Apparatus, School of Polymer Science and Engineering, Sichuan University, Chengdu, China
| | - Chunxia Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Yuqin Yao
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
- Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jiayuan Li
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
| | - Zhenmi Liu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
- Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xia Jiang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Ben Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China-Peking Union Medical College C.C. Chen Institute of Health, West China School of Public Health, and West China Fourth Hospital, Sichuan University, Chengdu
- Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
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11
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Choi J, Kim S, Kim J, Son HY, Yoo SK, Kim CU, Park YJ, Moon S, Cha B, Jeon MC, Park K, Yun JM, Cho B, Kim N, Kim C, Kwon NJ, Park YJ, Matsuda F, Momozawa Y, Kubo M, Biobank Japan Project, Kim HJ, Park JH, Seo JS, Kim JI, Im SW. A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants. SCIENCE ADVANCES 2023; 9:eadg6319. [PMID: 37556544 PMCID: PMC10411914 DOI: 10.1126/sciadv.adg6319] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 07/06/2023] [Indexed: 08/11/2023]
Abstract
Underrepresentation of non-European (EUR) populations hinders growth of global precision medicine. Resources such as imputation reference panels that match the study population are necessary to find low-frequency variants with substantial effects. We created a reference panel consisting of 14,393 whole-genome sequences including more than 11,000 Asian individuals. Genome-wide association studies were conducted using the reference panel and a population-specific genotype array of 72,298 subjects for eight phenotypes. This panel yields improved imputation accuracy of rare and low-frequency variants within East Asian populations compared with the largest reference panel. Thirty-nine previously unidentified associations were found, and more than half of the variants were East Asian specific. We discovered genes with rare protein-altering variants, including LTBP1 for height and GPR75 for body mass index, as well as putative regulatory mechanisms for rare noncoding variants with cell type-specific effects. We suggest that this dataset will add to the potential value of Asian precision medicine.
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Affiliation(s)
- Jaeyong Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | - Juhyun Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ho-Young Son
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Seong-Keun Yoo
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Young Jun Park
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sungji Moon
- Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Bukyoung Cha
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Min Chul Jeon
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyunghyuk Park
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Jae Moon Yun
- Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Belong Cho
- Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Family Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | | | | | - Young Joo Park
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | - Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | | | - Hyun-Jin Kim
- National Cancer Control Institute, National Cancer Center, Goyang, Republic of Korea
| | - Jin-Ho Park
- Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Family Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Sun Seo
- Macrogen Inc., Seoul, Republic of Korea
- Asian Genome Center, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sun-Wha Im
- Department of Biochemistry and Molecular Biology, Kangwon National University School of Medicine, Gangwon, Republic of Korea
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12
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Morimoto S, Takahashi S, Ito D, Daté Y, Okada K, Kato C, Nakamura S, Ozawa F, Chyi CM, Nishiyama A, Suzuki N, Fujimori K, Kondo T, Takao M, Hirai M, Kabe Y, Suematsu M, Jinzaki M, Aoki M, Fujiki Y, Sato Y, Suzuki N, Nakahara J, Okano H. Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery. Cell Stem Cell 2023; 30:766-780.e9. [PMID: 37267913 DOI: 10.1016/j.stem.2023.04.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 01/12/2023] [Accepted: 04/24/2023] [Indexed: 06/04/2023]
Abstract
iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.
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Affiliation(s)
- Satoru Morimoto
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Shinichi Takahashi
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology and Stroke, Saitama Medical University International Medical Center, Saitama 350-1298, Japan
| | - Daisuke Ito
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yugaku Daté
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kensuke Okada
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Chris Kato
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Shiho Nakamura
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Fumiko Ozawa
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Chai Muh Chyi
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Keio University Global Research Institute, Tokyo 108-8345, Japan
| | - Ayumi Nishiyama
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Naoki Suzuki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Koki Fujimori
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tosho Kondo
- Research Center of Neurology, ONO Pharmaceutical Co., Ltd., Osaka 541-8564, Japan
| | - Masaki Takao
- Department of Clinical Laboratory, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-0031, Japan; Department of Neurology, Mihara Memorial Hospital, Isesaki, Gunmma 372-0006, Japan
| | - Miwa Hirai
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yasuaki Kabe
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masahiro Jinzaki
- Department of Radiology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masashi Aoki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Yuto Fujiki
- Keio University Hospital Clinical and Translational Research Center, Tokyo 160-8582, Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Norihiro Suzuki
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Jin Nakahara
- Department of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
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13
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Dobson DA, Holle LA, Lin FC, Huffman JE, Luyendyk JP, Flick MJ, Smith NL, de Vries PS, Morrison AC, Wolberg AS. Novel genetic regulators of fibrinogen synthesis identified by an in vitro experimental platform. J Thromb Haemost 2023; 21:522-533. [PMID: 36696182 PMCID: PMC10111212 DOI: 10.1016/j.jtha.2022.10.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/06/2022] [Accepted: 10/26/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND Fibrinogen has an established, essential role in both coagulation and inflammatory pathways, and these processes are deeply intertwined in the development of thrombotic and atherosclerotic diseases. Previous studies aimed to better understand the (patho) physiological actions of fibrinogen by characterizing the genomic contribution to circulating fibrinogen levels. OBJECTIVES Establish an in vitro approach to define functional roles between genes within these loci and fibrinogen synthesis. METHODS Candidate genes were selected on the basis of their proximity to genetic variants associated with fibrinogen levels and expression in hepatocytes and HepG2 cells. HepG2 cells were transfected with small interfering RNAs targeting candidate genes and cultured in the absence or presence of the proinflammatory cytokine interleukin-6. Effects on fibrinogen protein production, gene expression, and cell growth were assessed by immunoblotting, real-time polymerase chain reaction, and cell counts, respectively. RESULTS HepG2 cells secreted fibrinogen, and stimulation with interleukin-6 increased fibrinogen production by 3.4 ± 1.2 fold. In the absence of interleukin-6, small interfering RNA knockdown of FGA, IL6R, or EEPD1 decreased fibrinogen production, and knockdown of LEPR, PDIA5, PLEC, SHANK3, or CPS1 increased production. In the presence of interleukin-6, knockdown of FGA, IL6R, or ATXN2L decreased fibrinogen production. Knockdown of FGA, IL6R, EEPD1, LEPR, PDIA5, PLEC, or CPS1 altered transcription of one or more fibrinogen genes. Knocking down ATXN2L suppressed inducible but not basal fibrinogen production via a post-transcriptional mechanism. CONCLUSIONS We established an in vitro platform to define the impact of select gene products on fibrinogen production. Genes identified in our screen may reveal cellular mechanisms that drive fibrinogen production as well as fibrin(ogen)-mediated (patho)physiological mechanisms.
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Affiliation(s)
- Dre'Von A Dobson
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA
| | - Lori A Holle
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA
| | - Feng-Chang Lin
- Department of Biostatistics and North Carolina Translational and Clinical Sciences Institute, University of North Carolina at Chapel Hill, NC, USA
| | | | - James P Luyendyk
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Matthew J Flick
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA
| | - Nicholas L Smith
- Department of Epidemiology, University of Washington, Seattle WA, USA; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle WA, USA; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Paul S de Vries
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA, USA
| | - Alanna C Morrison
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle WA, USA
| | - Alisa S Wolberg
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA.
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14
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Carmo-Silva S, Ferreira-Marques M, Nóbrega C, Botelho M, Costa D, Aveleira CA, Pulst SM, Pereira de Almeida L, Cavadas C. Ataxin-2 in the hypothalamus at the crossroads between metabolism and clock genes. J Mol Endocrinol 2023; 70:JME-21-0272. [PMID: 36103139 DOI: 10.1530/jme-21-0272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 09/14/2022] [Indexed: 01/19/2023]
Abstract
ATXN2 gene, encoding for ataxin-2, is located in a trait locus for obesity. Atxn2 knockout (KO) mice are obese and insulin resistant; however, the cause for this phenotype is still unknown. Moreover, several findings suggest ataxin-2 as a metabolic regulator, but the role of this protein in the hypothalamus was never studied before. The aim of this work was to understand if ataxin-2 modulation in the hypothalamus could play a role in metabolic regulation. Ataxin-2 was overexpressed/re-established in the hypothalamus of C57Bl6/Atxn2 KO mice fed either a chow or a high-fat diet (HFD). This delivery was achieved through stereotaxic injection of lentiviral vectors encoding for ataxin-2. We show, for the first time, that HFD decreases ataxin-2 levels in mouse hypothalamus and liver. Specific hypothalamic ataxin-2 overexpression prevents HFD-induced obesity and insulin resistance. Ataxin-2 re-establishment in Atxn2 KO mice improved metabolic dysfunction without changing body weight. Furthermore, we observed altered clock gene expression in Atxn2 KO that might be causative of metabolic dysfunction. Interestingly, ataxin-2 hypothalamic re-establishment rescued these circadian alterations. Thus, ataxin-2 in the hypothalamus is a determinant for weight, insulin sensitivity and clock gene expression. Ataxin-2's potential role in the circadian clock, through the regulation of clock genes, might be a relevant mechanism to regulate metabolism. Overall, this work shows hypothalamic ataxin-2 as a new player in metabolism regulation, which might contribute to the development of new strategies for metabolic disorders.
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Affiliation(s)
- Sara Carmo-Silva
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- MIA - Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
| | - Marisa Ferreira-Marques
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Clévio Nóbrega
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- ABC-RI, Algarve Biomedical Center Research Institute, Faro, Portugal
- Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Faro, Portugal
| | - Mariana Botelho
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Daniela Costa
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Célia A Aveleira
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- MIA - Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
| | - Stefan M Pulst
- Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Luís Pereira de Almeida
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Claudia Cavadas
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
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15
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Hartmann H, Ho WY, Chang JC, Ling SC. Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon? FEBS J 2022; 289:7688-7709. [PMID: 34469619 DOI: 10.1111/febs.16175] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/10/2021] [Accepted: 08/31/2021] [Indexed: 01/14/2023]
Abstract
Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease, is characterized by the selective degeneration of motor neurons leading to paralysis and eventual death. Multiple pathogenic mechanisms, including systemic dysmetabolism, have been proposed to contribute to ALS. Among them, dyslipidemia, i.e., abnormal level of cholesterol and other lipids in the circulation and central nervous system (CNS), has been reported in ALS patients, but without a consensus. Cholesterol is a constituent of cellular membranes and a precursor of steroid hormones, oxysterols, and bile acids. Consequently, optimal cholesterol levels are essential for health. Due to the blood-brain barrier (BBB), cholesterol cannot move between the CNS and the rest of the body. As such, cholesterol metabolism in the CNS is proposed to operate autonomously. Despite its importance, it remains elusive how cholesterol dyshomeostasis may contribute to ALS. In this review, we aim to describe the current state of cholesterol metabolism research in ALS, identify unresolved issues, and provide potential directions.
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Affiliation(s)
- Hannelore Hartmann
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wan Yun Ho
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jer-Cherng Chang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shuo-Chien Ling
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Healthy Longevity Translational Research Programme, National University Health System, Singapore, Singapore.,Program in Neuroscience and Behavior Disorders, Duke-NUS Medical School, Singapore, Singapore
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16
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ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity. J Immunol Res 2022; 2022:6863240. [PMID: 36213324 PMCID: PMC9535133 DOI: 10.1155/2022/6863240] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/26/2022] [Accepted: 08/22/2022] [Indexed: 11/25/2022] Open
Abstract
As one of the primary therapeutic choices, chemotherapy is widely adopted for progressive gastric cancer (GC), but the development of chemoresistance has limited chemotherapy efficacy and partly contributes to poor prognosis. Immunotherapy is increasingly being applied in the clinical treatment of GC and is also benefitting patients. To ascertain whether ATXN2 affects chemotherapy efficacy in GC cells and its role in GC immune escape, we performed high-throughput sequencing to clarify genes differentially expressed between 5-FU-resistant and 5-FU-sensitive GC cells and then conducted qRT–PCR to assess ATXN2 expression in GC tissues. Furthermore, the influence of ATXN2 on resistance was studied in vitro and in vivo, ATXN2 and other protein expression levels were detected using Western blotting and immunohistochemistry (IHC), and the direct association of SP1 and ATXN2 was confirmed through luciferase reporter gene analysis. We found elevated ATXN2 in GC tumors and a negative correlation between ATXN2 levels and the prognosis of GC. Furthermore, by activating the PI3K/AKT pathway, ATXN2 was found to promote chemoresistance in GC, facilitating BCL2L1 expression. In GC cells, ATXN2 further stimulated PD-L1 expression and provided better immunotherapy efficacy. Finally, we demonstrated that SP1 transcriptionally regulated the expression of ATXN2 and prompted GC chemoresistance and immune escape. In conclusion, our study reveals the important roles of the SP1/ATXN2/PI3K-AKT/BCL2L1 signalling pathway in GC chemoresistance and of the SP1/ATXN2/PI3K-AKT/PD-L1 signalling pathway in GC immunotherapy. Our findings provide new theories and experimental references for overcoming chemotherapy resistance in GC and enhancing the efficacy of immunotherapy for GC.
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17
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Zhang Y, Liu X, Zhang L, Wang L, He J, Ma H, Wang L. Preliminary identification and analysis of differential RNA editing between higher and lower backfat thickness pigs using DNA-seq and RNA-seq data. Anim Genet 2022; 53:327-339. [PMID: 35342974 DOI: 10.1111/age.13193] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 12/24/2021] [Accepted: 03/03/2022] [Indexed: 12/31/2022]
Abstract
RNA editing is an essential post-transcriptional regulatory mechanism. However, few studies have investigated the functional RNA edits in the economic traits of livestock on a genome-wide scale. Pigs are one of the most important livestock species and their fat is the principal organ involved in the regulation of adipose deposition. Here, we used three full-sibling pairs, with each pair comprising a pig with higher backfat (BF) thickness and lower backfat thickness, to identify RNA editing events based on whole-genome and transcriptome sequencing data. A total of 60,903 non-redundant RNA editing sites with 59,472 (97.7%) A-to-G edits were detected using a revised bioinformatics pipeline. A specific sequence context with G preference was found one base downstream of the edited site, and the editing level was associated with the distribution of nucleotides across nearly sites. Moreover, the A-to-G editing sites mostly occurred in the pig-special short interspersed nuclear elements, Pre0_SS. Comparing the difference between pigs with higher BF and lower BF, we found 211 differentially edited sites (DESites). Functional enrichment analyses revealed a significant enrichment of genes containing DESites in terms of adipose deposition. The DESites located in the six adipose-related genes (SKP1, GSK3B, COL5A3, MDM4, NT5C2, and DENND2A) were selected as candidate RNA editing sites associated with adipose deposition, and thus require further evaluation. This study mined the potentially functional RNA editing sites in pig adipose tissue and indicated that RNA editing may play an important role in adipose deposition, which provides a new insight into the post-transcriptionally mediated regulation mechanism of fat development.
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Affiliation(s)
- Yuebo Zhang
- College of Animal Science and Technology, Hunan Provincial Key Laboratory for Genetic Improvement of Domestic Animal, Hunan Agricultural University, Changsha, China
| | - Xin Liu
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Longchao Zhang
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Ligang Wang
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Jun He
- College of Animal Science and Technology, Hunan Provincial Key Laboratory for Genetic Improvement of Domestic Animal, Hunan Agricultural University, Changsha, China
| | - Haiming Ma
- College of Animal Science and Technology, Hunan Provincial Key Laboratory for Genetic Improvement of Domestic Animal, Hunan Agricultural University, Changsha, China
| | - Lixian Wang
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences, Beijing, China
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18
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Sundberg CA, Lakk M, Paul S, Figueroa KP, Scoles DR, Pulst SM, Križaj D. The RNA-binding protein and stress granule component ATAXIN-2 is expressed in mouse and human tissues associated with glaucoma pathogenesis. J Comp Neurol 2022; 530:537-552. [PMID: 34350994 PMCID: PMC8716417 DOI: 10.1002/cne.25228] [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: 04/22/2021] [Accepted: 07/06/2021] [Indexed: 02/03/2023]
Abstract
Polyglutamine repeat expansions in the Ataxin-2 (ATXN2) gene were first implicated in Spinocerebellar Ataxia Type 2, a disease associated with degeneration of motor neurons and Purkinje cells. Recent studies linked single nucleotide polymorphisms in the gene to elevated intraocular pressure in primary open angle glaucoma (POAG); yet, the localization of ATXN2 across glaucoma-relevant tissues of the vertebrate eye has not been thoroughly examined. This study characterizes ATXN2 expression in the mouse and human retina, and anterior eye, using an antibody validated in ATXN2-/- retinas. ATXN2-ir was localized to cytosolic sub compartments in retinal ganglion cell (RGC) somata and proximal dendrites in addition to GABAergic, glycinergic, and cholinergic amacrine cells in the inner plexiform layer (IPL) and displaced amacrine cells. Human, but not mouse retinas showed modest immunolabeling of bipolar cells. ATXN2 immunofluorescence was prominent in the trabecular meshwork and pigmented and nonpigmented cells of the ciliary body, with analyses of primary human trabecular meshwork cells confirming the finding. The expression of ATXN2 in key POAG-relevant ocular tissues supports the potential role in autophagy and stress granule formation in response to ocular hypertension.
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Affiliation(s)
- Chad A. Sundberg
- Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, USA
- Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Monika Lakk
- Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Sharan Paul
- Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Karla P. Figueroa
- Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Daniel R. Scoles
- Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Stefan M. Pulst
- Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - David Križaj
- Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, Utah, USA
- Department of Bioengineering, University of Utah, Salt Lake City, Utah, USA
- Department of Neurobiology & Anatomy, University of Utah, Salt Lake City, Utah, USA
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19
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Dávalos-Rodríguez NO, Rincón-Sánchez AR, Madrigal Ruiz PM, Flores-Alvarado LJ, López-Toledo S, Villafán-Bernal JR, Castro-Juárez CJ, Guzmán-López R, Siliceo-Murrieta JI, Ramirez-Garcia SA. VNTR (CAG)n polymorphism of the ATXN2 gene and metabolic parameters of cardiovascular risk associated with the degree of obesity in the Amerindian population of Oaxaca. ENDOCRINOL DIAB NUTR 2022; 69:15-24. [PMID: 35232555 DOI: 10.1016/j.endien.2021.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 04/13/2021] [Indexed: 06/14/2023]
Abstract
INTRODUCTION The ATXN2 gene has a VNTR (CAG)n with locus in exon1. Long alleles within the normal range (22-29 repeats) are associated with severe obesity in people from the United Kingdom, Indonesia and the Caribbean. OBJECTIVE To analyse the influence of VNTR (CAG)n on metabolic profile in adults with obesity and pre-obesity, as well as to estimate its effect on the risk of developing diabetes. METHODS AND MATERIAL 255 adults of Chinantec Amerindian ethnic origin were included, who underwent anthropometric and biochemical evaluation. The VNTR was amplified by end-point PCR and by 8% PAGE electrophoresis. RESULTS Differences were found in the waist/hip circumference index and body mass index in the carriers of genotypes different to the one homozygous for 22 repeats with a Student's t-test value of 0.0041 and 0.0334, respectively. We also found an association with a family history of chronic disease. CONCLUSION The VNTR of ATXN2 is associated with obesity in Mexican adults of Chinantec ancestry.
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Affiliation(s)
- Nory O Dávalos-Rodríguez
- Instituto de Genética Humana Dr. Enrique Corona Rivera, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Ana Rosa Rincón-Sánchez
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Perla Montserrat Madrigal Ruiz
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Luis Javier Flores-Alvarado
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | | | | | | | | | | | - Sergio Alberto Ramirez-Garcia
- Instituto de Nutrición, Universidad de la Sierra Sur, Oaxaca, Mexico; Maestría en Salud Pública, División de Estudios de Posgrado, Universidad de la Sierra Sur, Oaxaca, Mexico.
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20
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Vázquez-Mojena Y, León-Arcia K, González-Zaldivar Y, Rodríguez-Labrada R, Velázquez-Pérez L. Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and Perspectives. Mov Disord 2021; 36:2731-2744. [PMID: 34628681 DOI: 10.1002/mds.28819] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/02/2021] [Accepted: 09/06/2021] [Indexed: 12/11/2022] Open
Abstract
Polyglutamine spinocerebellar ataxias (SCAs) comprise a heterogeneous group of six autosomal dominant ataxias caused by cytosine-adenine-guanine repeat expansions in the coding region of single genes. Currently, there is no curative or disease-slowing treatment for these disorders, but their monogenic inheritance has informed rationales for development of gene therapy strategies. In fact, RNA interference strategies have shown promising findings in cellular and/or animal models of SCA1, SCA3, SCA6, and SCA7. In addition, antisense oligonucleotide therapy has provided encouraging proofs of concept in models of SCA1, SCA2, SCA3, and SCA7, but they have not yet progressed to clinical trials. On the contrary, the gene editing strategies, such as the clustered regularly interspaced short palindromic repeat (CRISPR/Cas9), have been introduced to a limited extent in these disorders. In this article, we review the available literature about gene therapy in polyglutamine SCAs and discuss the main technological and ethical challenges toward the prospect of their use in future clinical trials. Although antisense oligonucleotide therapies are further along the path to clinical phases, the recent failure of three clinical trials in Huntington's disease may delay their utilization for polyglutamine SCAs, but they offer lessons that could optimize the likelihood of success in potential future clinical studies. © 2021 International Parkinson and Movement Disorder Society.
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21
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Dávalos-Rodríguez NO, Rincón-Sánchez AR, Madrigal Ruiz PM, Flores-Alvarado LJ, López-Toledo S, Villafán-Bernal JR, Castro-Juárez CJ, Guzmán-López R, Siliceo-Murrieta JI, Ramírez-García SA. VNTR (CAG)n polymorphism of the ATXN2 gene and metabolic parameters of cardiovascular risk associated with the degree of obesity in the Amerindian population of Oaxaca. ENDOCRINOL DIAB NUTR 2021; 69:S2530-0164(21)00186-5. [PMID: 34400105 DOI: 10.1016/j.endinu.2021.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 03/05/2021] [Accepted: 04/13/2021] [Indexed: 11/28/2022]
Abstract
INTRODUCTION The ATXN2 gene has a VNTR (CAG)n with locus in exon1. Long alleles within the normal range (22-29 repeats) are associated with severe obesity in people from the United Kingdom, Indonesia and the Caribbean. OBJECTIVE To analyse the influence of VNTR (CAG)n on metabolic profile in adults with obesity and pre-obesity, as well as to estimate its effect on the risk of developing diabetes. METHODS AND MATERIAL 255 adults of Chinantec Amerindian ethnic origin were included, who underwent anthropometric and biochemical evaluation. The VNTR was amplified by end-point PCR and by 8% PAGE electrophoresis. RESULTS Differences were found in the waist/hip circumference index and body mass index in the carriers of genotypes different to the one homozygous for 22 repeats with a Student's t test value of 0.0041 and 0.0334, respectively. We also found an association with a family history of chronic disease. CONCLUSION The VNTR of ATXN2 is associated with obesity in Mexican adults of Chinantec ancestry.
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Affiliation(s)
- Nory O Dávalos-Rodríguez
- Instituto de Genética Humana Dr. Enrique Corona Rivera, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Ana Rosa Rincón-Sánchez
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Perla Montserrat Madrigal Ruiz
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Luis Javier Flores-Alvarado
- IBMMTG, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, México
| | | | | | | | | | | | - Sergio Alberto Ramírez-García
- Instituto de Nutrición, Universidad de la Sierra Sur, Oaxaca, México; Maestría en Salud Pública, División de Estudios de Posgrado, Universidad de la Sierra Sur, Oaxaca, México.
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22
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Scoles DR, Dansithong W, Pflieger LT, Paul S, Gandelman M, Figueroa KP, Rigo F, Bennett CF, Pulst SM. ALS-associated genes in SCA2 mouse spinal cord transcriptomes. Hum Mol Genet 2021; 29:1658-1672. [PMID: 32307524 PMCID: PMC7322574 DOI: 10.1093/hmg/ddaa072] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
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Affiliation(s)
- Daniel R Scoles
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA
| | - Warunee Dansithong
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA
| | - Lance T Pflieger
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA.,Department of Biomedical Informatics, University of Utah, 421 Wakara Way, Salt Lake City, UT 84108, USA
| | - Sharan Paul
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA
| | - Mandi Gandelman
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA
| | - Karla P Figueroa
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA
| | - Frank Rigo
- Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - C Frank Bennett
- Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - Stefan M Pulst
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA
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23
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Almaguer-Mederos LE, Aguilera-Rodríguez R, Almaguer-Gotay D, Hechavarría-Barzaga K, Álvarez-Sosa A, Chapman-Rodríguez Y, Silva-Ricardo Y, González-Zaldivar Y, Vázquez-Mojena Y, Cuello-Almarales D, Rodríguez-Estupiñán A. Testosterone Levels Are Decreased and Associated with Disease Duration in Male Spinocerebellar Ataxia Type 2 Patients. THE CEREBELLUM 2021; 19:597-604. [PMID: 32440846 DOI: 10.1007/s12311-020-01134-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder due to an unstable expansion of a CAG repeat in the ATXN2 gene. Despite clinical and experimental evidence indicating the relevance of the gonadotropic axis to the prognosis and therapeutics for several late-onset neurodegenerative disorders, its functioning and association with disease severity have not been previously explored in SCA2. To assess serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), and their clinical relevance in SCA2 patients. A case-control study involving 94 Cuban SCA2 patients and 101 gender- and age-matched healthy controls was conducted. Testosterone, LH, and FSH serum levels were determined by radioimmunoassay or immunoradiometric assay systems. Clinical outcomes included age at onset, disease duration, Scale for the Assessment and Rating of Ataxia (SARA) score, and progression rate. Univariate general linear models were generated. Testosterone, LH, and FSH serum levels were significantly reduced in male SCA2 patients relative to control individuals. On average, there was a 35% reduction in testosterone levels in male patients versus male control individuals. Testosterone levels were associated with disease duration (r = 0.383; p = 0.025) and age at onset (r = 0.414; p = 0.011) in male SCA2 patients, but no association was observed between testosterone and CAG expansion size, SARA score, or progression rate. Testosterone levels might be a biomarker of disease progression in male SCA2 patients. Further studies are needed to explore the effects of low testosterone levels on non-motor symptoms, and to assess the potential of testosterone replacement therapy in male SCA2 patients.
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Affiliation(s)
- Luis E Almaguer-Mederos
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba.
| | - Raúl Aguilera-Rodríguez
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
| | - Dennis Almaguer-Gotay
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
| | | | | | | | | | | | - Yaimé Vázquez-Mojena
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
| | - Dany Cuello-Almarales
- Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguin, Cuba
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24
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Rodriguez-Graña T, Rodríguez-Labrada R, Santana-Porbén S, Reynaldo-Cejas L, Medrano-Montero J, Canales-Ochoa N, Silva-Ricardo Y, Torres-Vega R, González-Zaldivar Y, Almaguer-Gotay D, Auburger G, Velázquez-Pérez L. Weight loss is correlated with disease severity in Spinocerebellar ataxia type 2: a cross-sectional cohort study. Nutr Neurosci 2021; 25:1747-1755. [PMID: 33687306 DOI: 10.1080/1028415x.2021.1895479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Body weight changes occur frequently during advanced stages of Spinocerebellar Ataxia type 2 (SCA2), nevertheless limited information exists on biomarkers of nutritional status of these patients. OBJECTIVE. To assess changes in surrogate nutritional markers of SCA2 patients; to explore their associations with expanded CAG repeats and disease severity. METHODS One-hundred-thirteen SCA2 patients and 50 healthy controls underwent a comprehensive anthropometrical and biochemical assessment protocol of the nutritional status. Neurological and genotype assessments were also performed. RESULTS A decrease in weight, body mass index (BMI), cutaneous skinfold thickness, fat mass, arm muscle circumference, calf circumference and skeletal muscle mass was observed in SCA2 patients compared to the controls. The total/HDL cholesterol ratio was significantly reduced in patients. BMI was correlated with the age at onset. Overall, anthropometric measures were correlated with clinical markers of disease severity and were more evident in severe and moderate cases. CONCLUSIONS Using anthropometric measures in the assessment of the nutritional status of SCA2 patients might provide hints about pathophysiological mechanisms that underlie metabolic abnormalities in SCA2. Anthropometric are close related with disease severity and progression, and trigger preventive therapies aimed to ameliorate weight loss and wasting in these patients.
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Affiliation(s)
- Tania Rodriguez-Graña
- Centre for the Research and Rehabilitation of Hereditary Ataxias, El Llano, Holguin, Cuba.,Medical University of Holguin, Holguin, Cuba
| | - Roberto Rodríguez-Labrada
- Centre for the Research and Rehabilitation of Hereditary Ataxias, El Llano, Holguin, Cuba.,Cuban Neuroscience Centre, La Havana, Cuba
| | | | - Lorenzo Reynaldo-Cejas
- Centre for the Research and Rehabilitation of Hereditary Ataxias, El Llano, Holguin, Cuba
| | | | - Nalia Canales-Ochoa
- Centre for the Research and Rehabilitation of Hereditary Ataxias, El Llano, Holguin, Cuba
| | | | - Reidenis Torres-Vega
- Centre for the Research and Rehabilitation of Hereditary Ataxias, El Llano, Holguin, Cuba
| | | | - Dennis Almaguer-Gotay
- Centre for the Research and Rehabilitation of Hereditary Ataxias, El Llano, Holguin, Cuba
| | - Georg Auburger
- Exp. Neurology, Medical Faculty, Goethe University, Frankfurt am Main, Germany
| | - Luis Velázquez-Pérez
- Centre for the Research and Rehabilitation of Hereditary Ataxias, El Llano, Holguin, Cuba.,Cuban Academy of Sciences, La Habana, Cuba
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25
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Canet-Pons J, Sen NE, Arsović A, Almaguer-Mederos LE, Halbach MV, Key J, Döring C, Kerksiek A, Picchiarelli G, Cassel R, René F, Dieterlé S, Fuchs NV, König R, Dupuis L, Lütjohann D, Gispert S, Auburger G. Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression. Neurobiol Dis 2021; 152:105289. [PMID: 33577922 DOI: 10.1016/j.nbd.2021.105289] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/11/2020] [Accepted: 02/03/2021] [Indexed: 12/12/2022] Open
Abstract
Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology. Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1 and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies.
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Affiliation(s)
- Júlia Canet-Pons
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany
| | - Nesli-Ece Sen
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany; Faculty of Biosciences, Goethe University, 60438 Frankfurt am Main, Germany
| | - Aleksandar Arsović
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany
| | - Luis-Enrique Almaguer-Mederos
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany; Center for Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguín, Cuba
| | - Melanie V Halbach
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany
| | - Jana Key
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany; Faculty of Biosciences, Goethe University, 60438 Frankfurt am Main, Germany
| | - Claudia Döring
- Dr. Senckenberg Institute of Pathology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany
| | - Anja Kerksiek
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Nordrhein-Westfalen, Germany
| | - Gina Picchiarelli
- UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France
| | - Raphaelle Cassel
- UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France
| | - Frédérique René
- UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France
| | - Stéphane Dieterlé
- UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France
| | - Nina V Fuchs
- Host-Pathogen Interactions, Paul-Ehrlich-Institute, 63225 Langen, Germany
| | - Renate König
- Host-Pathogen Interactions, Paul-Ehrlich-Institute, 63225 Langen, Germany
| | - Luc Dupuis
- UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Nordrhein-Westfalen, Germany
| | - Suzana Gispert
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany
| | - Georg Auburger
- Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany.
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26
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Almaguer-Mederos LE, Pérez-Ávila I, Aguilera-Rodríguez R, Velázquez-Garcés M, Almaguer-Gotay D, Hechavarría-Pupo R, Rodríguez-Estupiñán A, Auburger G. Body Mass Index Is Significantly Associated With Disease Severity in Spinocerebellar Ataxia Type 2 Patients. Mov Disord 2021; 36:1372-1380. [PMID: 33548146 DOI: 10.1002/mds.28498] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 12/09/2020] [Accepted: 12/21/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Spinocerebellar ataxia type 2 is a progressive neurodegenerative disorder due to an unstable expansion of a CAG repeat in the ATXN2 gene. Although weight loss has been associated with disease progression in several neurodegenerative conditions, it has been barely assessed in patients with spinocerebellar ataxia type 2. OBJECTIVE The objective of this study was to test whether body mass index is altered in patients with spinocerebellar ataxia type 2 with varying expansion sizes from early to late disease stages. METHODS A cross-sectional case-control study was performed, which included 222 clinically and molecularly diagnosed patients and 214 sex- and age-matched healthy individuals. ATXN2 genotypes and sex were considered as risk factors. Clinical outcomes included the body mass index, age at onset, disease duration, Scale for the Assessment and Rating of Ataxia score, disease stage, dysphagia, and progression rate. Multiple linear regression models were generated. RESULTS Body mass index was significantly decreased in male patients, but not in female patients, relative to control subjects. In addition to sex, body mass index was significantly associated with age at onset and progression rate. Conversely, body mass index, along with repeat length in ATXN2 expanded alleles and disease duration, was associated with Scale for the Assessment and Rating of Ataxia score. In addition, body mass index, along with the age at onset and the repeat length in ATXN2 normal and expanded alleles, has a significant influence on progression rate. CONCLUSIONS Body mass index might be a useful biomarker of disease severity, particularly in male patients with spinocerebellar ataxia type 2 in the context of nutritional interventions or clinical trials assessing the efficacy of promising new drugs. © 2021 International Parkinson and Movement Disorder Society.
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Affiliation(s)
| | - Ilbedis Pérez-Ávila
- Center for the Investigation and Rehabilitation of Hereditary Ataxias, Holguín, Cuba.,Center for Sports Medicine, Holguín, Cuba
| | | | | | - Dennis Almaguer-Gotay
- Center for the Investigation and Rehabilitation of Hereditary Ataxias, Holguín, Cuba
| | | | | | - Georg Auburger
- Experimental Neurology, Goethe University Medical Faculty, Frankfurt, Germany
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27
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Dodge JC, Yu J, Sardi SP, Shihabuddin LS. Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis. Sci Rep 2021; 11:803. [PMID: 33436868 PMCID: PMC7804278 DOI: 10.1038/s41598-020-80378-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Aberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.
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Affiliation(s)
- James C Dodge
- Rare and Neurological Diseases Therapeutic Area, Sanofi R+D, 49 New York Avenue, Framingham, MA, 01701, USA.
| | - Jinlong Yu
- Rare and Neurological Diseases Therapeutic Area, Sanofi R+D, 49 New York Avenue, Framingham, MA, 01701, USA
| | - S Pablo Sardi
- Rare and Neurological Diseases Therapeutic Area, Sanofi R+D, 49 New York Avenue, Framingham, MA, 01701, USA
| | - Lamya S Shihabuddin
- Rare and Neurological Diseases Therapeutic Area, Sanofi R+D, 49 New York Avenue, Framingham, MA, 01701, USA
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28
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Mao K, Zhang M, Cao J, Zhao X, Gao L, Fu L, Cheng H, Yan C, Xu X, Shi X, Jiang Z, Wang B, Zhang YB, Mi J. Coding Variants are Relevant to the Expression of Obesity-Related Genes for Pediatric Adiposity. Obesity (Silver Spring) 2021; 29:194-203. [PMID: 34494379 DOI: 10.1002/oby.23046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/09/2020] [Accepted: 09/09/2020] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Heredity has a remarkable effect on obesity in an obesogenic environment. Despite the numerous genetic variants that contribute to obesity-related traits, none has been identified in Chinese children. This study aimed to identify novel variants associated with childhood obesity in China. METHODS Promising single-nucleotide variants were obtained using whole-exome sequencing from 76 children who had obesity and 74 children with normal weight, and their associations with obesity-related traits in an additional 6,334-child cohort were investigated. The effects of the genome-wide significant (P < 5E-8) variants on the expression of the implicated genes in blood and adipose tissue were then depicted using transcriptome sequencing. RESULTS Two coding variants associated with obesity with genome-wide significance were identified: rs1059491 (P = 2.57E-28) in SULT1A2 and rs189326455 (P = 8.98E-12) in MAP3K21. In addition, rs1059491 was also significantly associated with several obesity traits. Transcriptome sequencing demonstrated that rs1059491 and rs189326455 were expression quantitative trait loci relevant to the expression levels of several obesity-related genes, such as SULT1A2, ATXN2L, TUFM, and MAP3K21. CONCLUSIONS This work identified two coding variants that were significantly associated with pediatric adiposity and were expression quantitative trait loci for obesity-related genes. This study provides new insights into the pathophysiology of Chinese childhood obesity.
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Affiliation(s)
- Ke Mao
- Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Meixian Zhang
- Department of Epidemiology, Capital Institute of Pediatrics, Beijing, China
| | - Jinshuai Cao
- Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Xiaoyuan Zhao
- Department of Epidemiology, Capital Institute of Pediatrics, Beijing, China
| | - Liwang Gao
- Department of Epidemiology, Capital Institute of Pediatrics, Beijing, China
| | - Liwan Fu
- National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Hong Cheng
- Department of Epidemiology, Capital Institute of Pediatrics, Beijing, China
| | - Chun Yan
- Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Xiaopeng Xu
- Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Xiaofeng Shi
- Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Zhuoyuan Jiang
- Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Bingqing Wang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yong-Biao Zhang
- Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Jie Mi
- National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
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29
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Wu X, Lin X, Li Q, Wang Z, Zhang N, Tian M, Wang X, Deng H, Tan H. Identification of novel SNPs associated with coronary artery disease and birth weight using a pleiotropic cFDR method. Aging (Albany NY) 2020; 13:3618-3644. [PMID: 33411684 PMCID: PMC7906162 DOI: 10.18632/aging.202322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 11/11/2020] [Indexed: 11/30/2022]
Abstract
Objectives: Clinical and epidemiological findings indicate an association between coronary artery disease (CAD) and low birth weight (BW). However, the mechanisms underlying this relationship are largely unknown. Here, we aimed to identify novel single-nucleotide polymorphisms (SNPs) associated with CAD, BW, and their shared pleiotropic loci, and to detect the potential causal relationship between CAD and BW. Methods: We first applied a genetic pleiotropic conditional false discovery rate (cFDR) method to two independent genome-wide association studies (GWAS) summary statistics of CAD and BW to estimate the pleiotropic enrichment between them. Then, bi-directional Mendelian randomization (MR) analyses were performed to clarify the causal association between these two traits. Results: By incorporating related traits into a conditional analysis framework, we observed the significant pleiotropic enrichment between CAD and BW. By applying the cFDR level of 0.05, 109 variants were detected for CAD, 203 for BW, and 26 pleiotropic variants for both traits. We identified 11 CAD- and/or BW-associated SNPs that showed more than three of the metabolic quantitative trait loci (metaQTL), protein QTL (pQTL), methylation QTL (meQTL), or expression QTL (eQTL) effects. The pleiotropic SNP rs10774625, located at ATXN2, showed metaQTL, pQTL, meQTL, and eQTL effects simultaneously. Using the bi-directional MR approach, we found a negative association from BW to CAD (odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.59 to 0.80, p = 1.57× 10-6). Conclusion: We identified several pleiotropic loci between CAD and BW by leveraging GWAS results of related phenotypes and identified a potential causal relationship from BW to CAD. Our findings provide novel insights into the shared biological mechanisms and overlapping genetic heritability between CAD and BW.
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Affiliation(s)
- Xinrui Wu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Xu Lin
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Qi Li
- Xiangxi Center for Disease Prevention and Control, Jishou 416000, China
| | - Zun Wang
- Xiangya Nursing School, Central South University, Changsha 410013, China
| | - Na Zhang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Mengyuan Tian
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Xiaolei Wang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Hongwen Deng
- School of Basic Medical Science, Central South University, Changsha 410013, China.,Tulane Center for Biomedical Informatics and Genomics, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Hongzhuan Tan
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, China
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30
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Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis. J Neurosci 2020; 40:9137-9147. [PMID: 33051352 DOI: 10.1523/jneurosci.1388-20.2020] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/31/2020] [Accepted: 08/28/2020] [Indexed: 12/14/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs in vitro Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1G93A mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1G93A mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS.SIGNIFICANCE STATEMENT Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Last, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS.
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31
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Arsović A, Halbach MV, Canet-Pons J, Esen-Sehir D, Döring C, Freudenberg F, Czechowska N, Seidel K, Baader SL, Gispert S, Sen NE, Auburger G. Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule-Purkinje Neuron Synaptic Strength. Int J Mol Sci 2020; 21:E6673. [PMID: 32932600 PMCID: PMC7555182 DOI: 10.3390/ijms21186673] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/07/2020] [Accepted: 09/10/2020] [Indexed: 12/13/2022] Open
Abstract
Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine expansion in Ataxin-2 (ATXN2). This factor binds RNA/proteins to modify metabolism after stress, and to control calcium (Ca2+) homeostasis after stimuli. Cerebellar ataxias and corticospinal motor neuron degeneration are determined by gain/loss in ATXN2 function, so we aimed to identify key molecules in this atrophic process, as potential disease progression markers. Our Atxn2-CAG100-Knock-In mouse faithfully models features observed in patients at pre-onset, early and terminal stages. Here, its cerebellar global RNA profiling revealed downregulation of signaling cascades to precede motor deficits. Validation work at mRNA/protein level defined alterations that were independent of constant physiological ATXN2 functions, but specific for RNA/aggregation toxicity, and progressive across the short lifespan. The earliest changes were detected at three months among Ca2+ channels/transporters (Itpr1, Ryr3, Atp2a2, Atp2a3, Trpc3), IP3 metabolism (Plcg1, Inpp5a, Itpka), and Ca2+-Calmodulin dependent kinases (Camk2a, Camk4). CaMKIV-Sam68 control over alternative splicing of Nrxn1, an adhesion component of glutamatergic synapses between granule and Purkinje neurons, was found to be affected. Systematic screening of pre/post-synapse components, with dendrite morphology assessment, suggested early impairment of CamKIIα abundance together with the weakening of parallel fiber connectivity. These data reveal molecular changes due to ATXN2 pathology, primarily impacting excitability and communication.
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Affiliation(s)
- Aleksandar Arsović
- Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (A.A.); (M.V.H.); (J.C.-P.); (S.G.)
| | - Melanie Vanessa Halbach
- Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (A.A.); (M.V.H.); (J.C.-P.); (S.G.)
| | - Júlia Canet-Pons
- Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (A.A.); (M.V.H.); (J.C.-P.); (S.G.)
| | - Dilhan Esen-Sehir
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Medical Faculty, Goethe University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main, Germany; (D.E.-S.); (F.F.)
- Faculty of Biosciences, Goethe-University, Max von Laue Strasse 9, 60438 Frankfurt am Main, Germany
| | - Claudia Döring
- Dr. Senckenberg Institute of Pathology, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany;
| | - Florian Freudenberg
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Medical Faculty, Goethe University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main, Germany; (D.E.-S.); (F.F.)
| | - Nicoletta Czechowska
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53115 Bonn, Germany; (N.C.); (K.S.); (S.L.B.)
| | - Kay Seidel
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53115 Bonn, Germany; (N.C.); (K.S.); (S.L.B.)
| | - Stephan L. Baader
- Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53115 Bonn, Germany; (N.C.); (K.S.); (S.L.B.)
| | - Suzana Gispert
- Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (A.A.); (M.V.H.); (J.C.-P.); (S.G.)
| | - Nesli-Ece Sen
- Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (A.A.); (M.V.H.); (J.C.-P.); (S.G.)
- Faculty of Biosciences, Goethe-University, Max von Laue Strasse 9, 60438 Frankfurt am Main, Germany
| | - Georg Auburger
- Experimental Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (A.A.); (M.V.H.); (J.C.-P.); (S.G.)
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32
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Key J, Harter PN, Sen NE, Gradhand E, Auburger G, Gispert S. Mid-Gestation lethality of Atxn2l-Ablated Mice. Int J Mol Sci 2020; 21:E5124. [PMID: 32698485 PMCID: PMC7404131 DOI: 10.3390/ijms21145124] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/10/2020] [Accepted: 07/16/2020] [Indexed: 12/11/2022] Open
Abstract
Depletion of yeast/fly Ataxin-2 rescues TDP-43 overexpression toxicity. In mouse models of Amyotrophic Lateral Sclerosis via TDP-43 overexpression, depletion of its ortholog ATXN2 mitigated motor neuron degeneration and extended lifespan from 25 days to >300 days. There is another ortholog in mammals, named ATXN2L (Ataxin-2-like), which is almost uncharacterized but also functions in RNA surveillance at stress granules. We generated mice with Crispr/Cas9-mediated deletion of Atxn2l exons 5-8, studying homozygotes prenatally and heterozygotes during aging. Our novel findings indicate that ATXN2L absence triggers mid-gestational embryonic lethality, affecting female animals more strongly. Weight and development stages of homozygous mutants were reduced. Placenta phenotypes were not apparent, but brain histology showed lamination defects and apoptosis. Aged heterozygotes showed no locomotor deficits or weight loss over 12 months. Null mutants in vivo displayed compensatory efforts to maximize Atxn2l expression, which were prevented upon nutrient abundance in vitro. Mouse embryonal fibroblast cells revealed more multinucleated giant cells upon ATXN2L deficiency. In addition, in human neural cells, transcript levels of ATXN2L were induced upon starvation and glucose and amino acids exposure, but this induction was partially prevented by serum or low cholesterol administration. Neither ATXN2L depletion triggered dysregulation of ATXN2, nor a converse effect was observed. Overall, this essential role of ATXN2L for embryogenesis raises questions about its role in neurodegenerative diseases and neuroprotective therapies.
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Affiliation(s)
- Jana Key
- Exp. Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (J.K.); (N.-E.S.)
- Faculty of Biosciences, Goethe-University, Altenhöferallee 1, 60438 Frankfurt am Main, Germany
| | - Patrick N. Harter
- Institute of Neurology (Edinger-Institute), University Hospital Frankfurt, Goethe University, Heinrich-Hoffmann-Strasse 7, 60528 Frankfurt am Main, Germany;
| | - Nesli-Ece Sen
- Exp. Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (J.K.); (N.-E.S.)
- Faculty of Biosciences, Goethe-University, Altenhöferallee 1, 60438 Frankfurt am Main, Germany
| | - Elise Gradhand
- Dr. Senckenberg Institute for Pathology, University Hospital, Goethe University, Theodor-Stern-Kai-7, 60590 Frankfurt am Main, Germany;
| | - Georg Auburger
- Exp. Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (J.K.); (N.-E.S.)
| | - Suzana Gispert
- Exp. Neurology, Medical Faculty, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (J.K.); (N.-E.S.)
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33
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Shadrina AS, Shashkova TI, Torgasheva AA, Sharapov SZ, Klarić L, Pakhomov ED, Alexeev DG, Wilson JF, Tsepilov YA, Joshi PK, Aulchenko YS. Prioritization of causal genes for coronary artery disease based on cumulative evidence from experimental and in silico studies. Sci Rep 2020; 10:10486. [PMID: 32591598 PMCID: PMC7320185 DOI: 10.1038/s41598-020-67001-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022] Open
Abstract
Genome-wide association studies have led to a significant progress in identification of genomic loci affecting coronary artery disease (CAD) risk. However, revealing the causal genes responsible for the observed associations is challenging. In the present study, we aimed to prioritize CAD-relevant genes based on cumulative evidence from the published studies and our own study of colocalization between eQTLs and loci associated with CAD using SMR/HEIDI approach. Prior knowledge of candidate genes was extracted from both experimental and in silico studies, employing different prioritization algorithms. Our review systematized information for a total of 51 CAD-associated loci. We pinpointed 37 genes in 36 loci. For 27 genes we infer they are causal for CAD, and for 10 further genes we judge them most likely causal. Colocalization analysis showed that for 18 out of these loci, association with CAD can be explained by changes in gene expression in one or more CAD-relevant tissues. Furthermore, for 8 out of 36 loci, existing evidence suggested additional CAD-associated genes. For the remaining 15 loci, we concluded that evidence for gene prioritization remains inconsistent, insufficient, or absent. Our results provide deeper insights into the genetic etiology of CAD and demonstrate knowledge gaps where further research is warranted.
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Affiliation(s)
- Alexandra S Shadrina
- Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, 630090, Russia. .,Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia.
| | - Tatiana I Shashkova
- Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, 630090, Russia.,Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, Moscow, 117303, Russia.,Research and Training Center on Bioinformatics, A.A. Kharkevich Institute for Information Transmission Problems, Moscow, 127051, Russia
| | - Anna A Torgasheva
- Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, 630090, Russia.,Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia
| | - Sodbo Z Sharapov
- Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, 630090, Russia.,Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia
| | - Lucija Klarić
- Genos Glycoscience Research Laboratory, Zagreb, Croatia.,MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, Scotland, UK
| | - Eugene D Pakhomov
- Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Dmitry G Alexeev
- Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, 630090, Russia
| | - James F Wilson
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, Scotland, UK.,Usher Institute, University of Edinburgh, Edinburgh, EH8 9AG, Scotland, UK
| | - Yakov A Tsepilov
- Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, 630090, Russia.,Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia
| | - Peter K Joshi
- Usher Institute, University of Edinburgh, Edinburgh, EH8 9AG, Scotland, UK
| | - Yurii S Aulchenko
- Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Novosibirsk, 630090, Russia. .,PolyOmica, 's-Hertogenbosch, 5237 PA, The Netherlands.
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Niewiadomska-Cimicka A, Hache A, Trottier Y. Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion. Front Neurosci 2020; 14:571. [PMID: 32581696 PMCID: PMC7296114 DOI: 10.3389/fnins.2020.00571] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022] Open
Abstract
Polyglutamine spinocerebellar ataxias (polyQ SCAs) include SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 and constitute a group of adult onset neurodegenerative disorders caused by the expansion of a CAG repeat sequence located within the coding region of specific genes, which translates into polyglutamine tract in the corresponding proteins. PolyQ SCAs are characterized by degeneration of the cerebellum and its associated structures and lead to progressive ataxia and other diverse symptoms. In recent years, gene and epigenetic deregulations have been shown to play a critical role in the pathogenesis of polyQ SCAs. Here, we provide an overview of the functions of wild type and pathogenic polyQ SCA proteins in gene regulation, describe the extent and nature of gene expression changes and their pathological consequences in diseases, and discuss potential avenues to further investigate converging and distinct disease pathways and to develop therapeutic strategies.
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Affiliation(s)
- Anna Niewiadomska-Cimicka
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.,Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.,Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.,Université de Strasbourg, Strasbourg, France
| | - Antoine Hache
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.,Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.,Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.,Université de Strasbourg, Strasbourg, France
| | - Yvon Trottier
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.,Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.,Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.,Université de Strasbourg, Strasbourg, France
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Pape JA, Grose JH. The effects of diet and sex in amyotrophic lateral sclerosis. Rev Neurol (Paris) 2020; 176:301-315. [PMID: 32147204 DOI: 10.1016/j.neurol.2019.09.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 09/30/2019] [Indexed: 12/11/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, suggesting there are multiple contributing factors that influence the disease risk, onset, and progression. Diet and sex are two factors that have been reported to alter ALS risk, onset and progression in humans and in animal models, providing potential modifiers of disease. Several epidemiological studies have identified diets that positively affect ALS patients, including various high-calorie fat or sugar-based diets, while animal models have been developed to test how these diets are working on a molecular level. These diets may offset the metabolic alterations that occur in ALS, such as hypermetabolism, lowered body mass index(BMI), and hyperlipidemia. Sex-dependent differences have also come forth from large-scale epidemiological studies as well as mouse-model studies. In addition, sex hormones have been shown to affect disease risk or progression. Herein, studies on the effects of diet and sex on ALS risk, onset, and progression will be reviewed. Understanding these diet- and sex-dependent outcomes may lead to optimized patient-specific therapies for ALS.
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Affiliation(s)
- J A Pape
- Department of Microbiology and Molecular Biology, Provo, United States
| | - J H Grose
- Department of Microbiology and Molecular Biology, Provo, United States.
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Hansen M, Zeddies S, Meinders M, di Summa F, Rollmann E, van Alphen FP, Hoogendijk AJ, Moore KS, Halbach M, Gutiérrez L, van den Biggelaar M, Thijssen-Timmer DC, Auburger GW, van den Akker E, von Lindern M. The RNA-Binding Protein ATXN2 is Expressed during Megakaryopoiesis and May Control Timing of Gene Expression. Int J Mol Sci 2020; 21:ijms21030967. [PMID: 32024018 PMCID: PMC7037754 DOI: 10.3390/ijms21030967] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/21/2020] [Accepted: 01/30/2020] [Indexed: 12/13/2022] Open
Abstract
Megakaryopoiesis is the process during which megakaryoblasts differentiate to polyploid megakaryocytes that can subsequently shed thousands of platelets in the circulation. Megakaryocytes accumulate mRNA during their maturation, which is required for the correct spatio-temporal production of cytoskeletal proteins, membranes and platelet-specific granules, and for the subsequent shedding of thousands of platelets per cell. Gene expression profiling identified the RNA binding protein ATAXIN2 (ATXN2) as a putative novel regulator of megakaryopoiesis. ATXN2 expression is high in CD34+/CD41+ megakaryoblasts and sharply decreases upon maturation to megakaryocytes. ATXN2 associates with DDX6 suggesting that it may mediate repression of mRNA translation during early megakaryopoiesis. Comparative transcriptome and proteome analysis on megakaryoid cells (MEG-01) with differential ATXN2 expression identified ATXN2 dependent gene expression of mRNA and protein involved in processes linked to hemostasis. Mice deficient for Atxn2 did not display differences in bleeding times, but the expression of key surface receptors on platelets, such as ITGB3 (carries the CD61 antigen) and CD31 (PECAM1), was deregulated and platelet aggregation upon specific triggers was reduced.
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Affiliation(s)
- Marten Hansen
- Department Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Centre, 1066CX Amsterdam, The Netherlands; (M.H.); (S.Z.); (F.d.S.); (K.S.M.); (D.C.T.-T.); (E.v.d.A.)
| | - Sabrina Zeddies
- Department Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Centre, 1066CX Amsterdam, The Netherlands; (M.H.); (S.Z.); (F.d.S.); (K.S.M.); (D.C.T.-T.); (E.v.d.A.)
| | - Marjolein Meinders
- Department Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam,1066CX Amsterdam, The Netherlands; (M.M.); (L.G.)
| | - Franca di Summa
- Department Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Centre, 1066CX Amsterdam, The Netherlands; (M.H.); (S.Z.); (F.d.S.); (K.S.M.); (D.C.T.-T.); (E.v.d.A.)
| | - Ewa Rollmann
- Experimental Neurology, Goethe University Medical School, 60528 Frankfurt am Main, Germany; (E.R.); (M.H.)
| | - Floris P.J. van Alphen
- Department of Molecular and Cellular Hemostasis, Sanquin Research, 1066CX Amsterdam, The Netherlands (A.J.H.); (M.v.d.B.)
| | - Arjan J. Hoogendijk
- Department of Molecular and Cellular Hemostasis, Sanquin Research, 1066CX Amsterdam, The Netherlands (A.J.H.); (M.v.d.B.)
| | - Kat S. Moore
- Department Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Centre, 1066CX Amsterdam, The Netherlands; (M.H.); (S.Z.); (F.d.S.); (K.S.M.); (D.C.T.-T.); (E.v.d.A.)
| | - Melanie Halbach
- Experimental Neurology, Goethe University Medical School, 60528 Frankfurt am Main, Germany; (E.R.); (M.H.)
| | - Laura Gutiérrez
- Department Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam,1066CX Amsterdam, The Netherlands; (M.M.); (L.G.)
| | - Maartje van den Biggelaar
- Department of Molecular and Cellular Hemostasis, Sanquin Research, 1066CX Amsterdam, The Netherlands (A.J.H.); (M.v.d.B.)
| | - Daphne C. Thijssen-Timmer
- Department Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Centre, 1066CX Amsterdam, The Netherlands; (M.H.); (S.Z.); (F.d.S.); (K.S.M.); (D.C.T.-T.); (E.v.d.A.)
| | - Georg W.J. Auburger
- Experimental Neurology, Goethe University Medical School, 60528 Frankfurt am Main, Germany; (E.R.); (M.H.)
| | - Emile van den Akker
- Department Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Centre, 1066CX Amsterdam, The Netherlands; (M.H.); (S.Z.); (F.d.S.); (K.S.M.); (D.C.T.-T.); (E.v.d.A.)
| | - Marieke von Lindern
- Department Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Centre, 1066CX Amsterdam, The Netherlands; (M.H.); (S.Z.); (F.d.S.); (K.S.M.); (D.C.T.-T.); (E.v.d.A.)
- Correspondence: ; Tel.: +31-6-1203-7801
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Velázquez-Pérez L, Medrano-Montero J, Rodríguez-Labrada R, Canales-Ochoa N, Campins Alí J, Carrillo Rodes FJ, Rodríguez Graña T, Hernández Oliver MO, Aguilera Rodríguez R, Domínguez Barrios Y, Torres Vega R, Flores Angulo L, Cordero Navarro NY, Sigler Villanueva AA, Gámez Rodríguez O, Sagaró Zambrano I, Navas Napóles NY, García Zacarías J, Serrano Barrera OR, Ramírez Bautista MB, Estupiñán Rodríguez A, Guerra Rondón LA, Vázquez-Mojena Y, González-Zaldivar Y, Almaguer Mederos LE, Leyva-Mérida A. Hereditary Ataxias in Cuba: A Nationwide Epidemiological and Clinical Study in 1001 Patients. THE CEREBELLUM 2020; 19:252-264. [DOI: 10.1007/s12311-020-01107-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Enhancement of Autophagy and Solubilization of Ataxin-2 Alleviate Apoptosis in Spinocerebellar Ataxia Type 2 Patient Cells. THE CEREBELLUM 2020; 19:165-181. [DOI: 10.1007/s12311-019-01092-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Sen NE, Arsovic A, Meierhofer D, Brodesser S, Oberschmidt C, Canet-Pons J, Kaya ZE, Halbach MV, Gispert S, Sandhoff K, Auburger G. In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism. Int J Mol Sci 2019; 20:E5854. [PMID: 31766565 PMCID: PMC6928749 DOI: 10.3390/ijms20235854] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 02/08/2023] Open
Abstract
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.
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Affiliation(s)
- Nesli-Ece Sen
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
- Faculty of Biosciences, Goethe-University, 60438 Frankfurt am Main, Germany
| | - Aleksandar Arsovic
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany;
| | - Susanne Brodesser
- Membrane Biology and Lipid Biochemistry Unit, Life and Medical Sciences Institute, University of Bonn, 53121 Bonn, Germany;
| | - Carola Oberschmidt
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
| | - Júlia Canet-Pons
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
| | - Zeynep-Ece Kaya
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
- Cerrahpasa School of Medicine, Istanbul University, 34098 Istanbul, Turkey
| | - Melanie-Vanessa Halbach
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
| | - Suzana Gispert
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
| | - Konrad Sandhoff
- Membrane Biology and Lipid Biochemistry Unit, Life and Medical Sciences Institute, University of Bonn, 53121 Bonn, Germany;
| | - Georg Auburger
- Experimental Neurology, Building 89, Goethe University Medical Faculty, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany; (N.-E.S.); (A.A.); (C.O.); (J.C.-P.); (Z.-E.K.); (M.-V.H.); (S.G.)
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Egorova PA, Bezprozvanny IB. Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2. Neurotherapeutics 2019; 16:1050-1073. [PMID: 31435879 PMCID: PMC6985344 DOI: 10.1007/s13311-019-00777-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.
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Affiliation(s)
- Polina A Egorova
- Laboratory of Molecular Neurodegeneration, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, 195251, Russia
| | - Ilya B Bezprozvanny
- Laboratory of Molecular Neurodegeneration, Peter the Great St.Petersburg Polytechnic University, St. Petersburg, 195251, Russia.
- Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, ND12.200, Dallas, Texas, 75390, USA.
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Internalization Characterization of Si Nanorod with Camouflaged Cell Membrane Proteins Reveals ATXN2 as a Negative Regulator. Cells 2019; 8:cells8080931. [PMID: 31430912 PMCID: PMC6721741 DOI: 10.3390/cells8080931] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/14/2019] [Accepted: 08/16/2019] [Indexed: 12/11/2022] Open
Abstract
The fabrication of shape-controlled nanocarriers is critical for efficient delivery of biomolecules across the cell membrane. Surface coating of the nanocarrier can improve internalization efficiency. Here, we developed a facile method of silicon nanorod fabrication leading to a controlled size and shape. We then systematically evaluated five surface modifications with membrane proteins from different cancer cell lines including MCF7, MD231, Hela, Panc-PDX, and Panc-1. We demonstrated that silicon nanorods coated with either a homolytic or heterolytic membrane protein coating have significantly improved internalization efficiency as compared with uncoated Si nanorods. To elucidate the molecular mechanism of the improved efficiency associated with a modified coating, we analyzed the coating membrane proteins derived from five cell lines with proteomics and identified 601 proteins shared by different cell sources. These proteins may function as cell-substrate adhesion molecules that contribute to the enhanced internalization. We also tested the internalization efficiency of nanorods with different coatings in each of the five cell lines to determine the influencing factors from target cells. We found that the internalization efficiency varied among different target cells, and the ranking of the average efficiency was as follows: Hela > Panc-PDX > MD231 > MCF7 > Panc-1. The bioinformatics analysis suggested that the low internalization efficiency in Panc-1 cells might be associated with the upregulation of ATXN2, which is a negative regulator of endocytosis. We further demonstrated that ATXN2 knockdown with specific siRNA significantly improved nanorod internalization efficiency in Panc-1 cells suggesting that ATXN2 can be a reference for efficiency prediction of nanoparticle delivery to tumor cells. Thus, we studied the effect of different cancer cell membrane proteins on nanorod uptake efficiencies. These results can improve nanorod internalization to cancer cells, including a fundamental understanding of the internalization efficiency of cancer cells.
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Sen NE, Canet-Pons J, Halbach MV, Arsovic A, Pilatus U, Chae WH, Kaya ZE, Seidel K, Rollmann E, Mittelbronn M, Meierhofer D, De Zeeuw CI, Bosman LWJ, Gispert S, Auburger G. Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation. Neurobiol Dis 2019; 132:104559. [PMID: 31376479 DOI: 10.1016/j.nbd.2019.104559] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/16/2019] [Accepted: 07/30/2019] [Indexed: 12/13/2022] Open
Abstract
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial molecular pathways. The ataxin-2 (ATXN2) protein is mainly involved in RNA translation control and regulation of nutrient metabolism during stress periods. The preferential mRNA targets of ATXN2 are yet to be determined. In order to understand the molecular disease mechanism throughout different prognostic stages, we generated an Atxn2-CAG100-knock-in (KIN) mouse model of SCA2 with intact murine ATXN2 expression regulation. Its characterization revealed somatic mosaicism of the expansion, with shortened lifespan, a progressive spatio-temporal pattern of pathology with subsequent phenotypes, and anomalies of brain metabolites such as N-acetylaspartate (NAA), all of which mirror faithfully the findings in SCA2 patients. Novel molecular analyses from stages before the onset of motor deficits revealed a strong selective effect of ATXN2 on Nat8l mRNA which encodes the enzyme responsible for NAA synthesis. This metabolite is a prominent energy store of the brain and a well-established marker for neuronal health. Overall, we present a novel authentic rodent model of SCA2, where in vivo magnetic resonance imaging was feasible to monitor progression and where the definition of earliest transcriptional abnormalities was possible. We believe that this model will not only reveal crucial insights regarding the pathomechanism of SCA2 and other ATXN2-associated disorders, but will also aid in developing gene-targeted therapies and disease prevention.
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Affiliation(s)
- Nesli-Ece Sen
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany
| | - Júlia Canet-Pons
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany
| | - Melanie V Halbach
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany
| | - Aleksandar Arsovic
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany
| | - Ulrich Pilatus
- Institute of Neuroradiology, Goethe University Medical School, 60590 Frankfurt am Main, Germany
| | - Woon-Hyung Chae
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
| | - Zeynep-Ece Kaya
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany; Department of Neurology, Cerrahpasa School of Medicine, Istanbul University, 34098 Istanbul, Turkey
| | - Kay Seidel
- Department of Anatomy II, Institute of Clinical Neuroanatomy, Goethe University, 60590 Frankfurt am Main, Germany
| | - Ewa Rollmann
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany
| | - Michel Mittelbronn
- Neurological Institute (Edinger Institute), Goethe University, 60590 Frankfurt am Main, Germany; Luxembourg Centre of Neuropathology (LCNP), Luxembourg; Department of Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Department of Oncology, NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
| | - Chris I De Zeeuw
- Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences, 1105 BA Amsterdam, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands
| | - Laurens W J Bosman
- Department of Neuroscience, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands
| | - Suzana Gispert
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany
| | - Georg Auburger
- Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
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Lastres-Becker I, Nonis D, Nowock J, Auburger G. New alternative splicing variants of the ATXN2 transcript. Neurol Res Pract 2019; 1:22. [PMID: 33324888 PMCID: PMC7650068 DOI: 10.1186/s42466-019-0025-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 05/09/2019] [Indexed: 12/12/2022] Open
Abstract
Background Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder with progressive degeneration of cerebellar Purkinje cells and selective loss of neurons in the brainstem. This neurodegenerative disorder is caused by the expansion of a polyglutamine domain in ataxin-2. Ataxin-2 is composed of 1312 amino acids, has a predicted molecular weight of 150-kDa and is widely expressed in neuronal and non-neuronal tissues. To date, the putative functions of ataxin-2 on mRNA translation and endocytosis remain ill-defined. Differential splicing with a lack of exons 10 and 21 was described in humans, and additional splicing of exon 11 in mice. In this study, we observed that the molecular size of transfected full-length wild-type ataxin-2 (22 glutamines) is different from endogenous ataxin-2 and that this variation could not be explained by the previously published splice variants alone. Methods Quantitative immunoblots and qualitative reverse-transcriptase polymerase-chain-reaction (RT-PCR) were used to characterize isoform variants, before sequencing was employed for validation. Results We report the characterization of further splice variants of ataxin-2 in different human cell lines and in mouse and human brain. Using RT-PCR from cell lines HeLa, HEK293 and COS-7 throughout the open reading frame of ataxin-2 together with PCR-sequencing, we found novel splice variants lacking exon 12 and exon 24. These findings were corroborated in murine and human brain. The splice variants were also found in human skin fibroblasts from SCA2 patients and controls, indicating that the polyglutamine expansion does not abolish the splicing. Conclusions Given that Ataxin-2 interacts with crucial splice modulators such as TDP-43 and modulates the risk of Amyotrophic Lateral Sclerosis, its own splice isoforms may become relevant in brain tissue to monitor the RNA processing during disease progression and neuroprotective therapy.
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Affiliation(s)
- Isabel Lastres-Becker
- Experimental Neurology, Goethe University Medical Faculty, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.,Present address: Department of Biochemistry, Faculty of Medicine, Universidad Autonoma of Madrid, Madrid, Spain
| | - David Nonis
- Experimental Neurology, Goethe University Medical Faculty, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
| | - Joachim Nowock
- Experimental Neurology, Goethe University Medical Faculty, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
| | - Georg Auburger
- Experimental Neurology, Goethe University Medical Faculty, Building 89, 3rd floor, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany
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Pulst SM. The complex structure of ATXN2 genetic variation. Neurol Genet 2018; 4:e299. [PMID: 30588499 PMCID: PMC6290488 DOI: 10.1212/nxg.0000000000000299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 11/02/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Stefan M Pulst
- Department of Neurology, University of Utah, Salt Lake City, UT
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45
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Repeat length variations in polyglutamine disease-associated genes affect body mass index. Int J Obes (Lond) 2018; 43:440-449. [PMID: 30120431 DOI: 10.1038/s41366-018-0161-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 05/15/2018] [Accepted: 06/15/2018] [Indexed: 11/08/2022]
Abstract
BACKGROUND The worldwide prevalence of obesity, a major risk factor for numerous debilitating chronic disorders, is increasing rapidly. Although a substantial amount of the variation in body mass index (BMI) is estimated to be heritable, the largest meta-analysis of genome-wide association studies (GWAS) to date explained only ~2.7% of the variation. To tackle this 'missing heritability' problem of obesity, here we focused on the contribution of DNA repeat length polymorphisms which are not detectable by GWAS. SUBJECTS AND METHODS We determined the cytosine-adenine-guanine (CAG) repeat length in the nine known polyglutamine disease-associated genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1 and AR) in two large cohorts consisting of 12,457 individuals and analyzed their association with BMI, using generalized linear mixed-effect models. RESULTS We found a significant association between BMI and the length of CAG repeats in seven polyglutamine disease-associated genes (including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP and AR). Importantly, these repeat variations could account for 0.75% of the total BMI variation. CONCLUSIONS Our findings incriminate repeat polymorphisms as an important novel class of genetic risk factors of obesity and highlight the role of the brain in its pathophysiology.
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THE LYSOSOMAL STORAGE DISEASE GM2 GANGLIOSIDOSIS IN CAPTIVE BANDED MONGOOSE SIBLINGS ( MUNGOS MUNGO). J Zoo Wildl Med 2018; 49:335-344. [PMID: 29900785 DOI: 10.1638/2017-0199.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
This study reports the occurrence of the lysosomal storage disease GM2 gangliosidosis (Sandhoff disease) in two 11-mo-old captive-bred, male and female mongoose siblings ( Mungos mungo). The clinical signs and the pathological findings reported here were similar to those reported in other mammalian species. Light microscopy revealed an accumulation of stored material in neurons and macrophages accompanied by a significant neuronal degeneration (swelling of neuronal soma, loss of Nissl substance, and neuronal loss) and gliosis. Electron microscopy of brain tissue identified the stored material as membrane-bound multilamellar bodies. An almost complete lack of total hexosaminidase activity in serum suggested a defect in the HEXB gene (Sandhoff disease in humans). High-performance thin-layer chromatography and mass spectrometry confirmed the accumulation of GM2 ganglioside in brain and kidney tissue, and the lectin staining pattern of the brain tissue further corroborated the diagnosis of a Sandhoff-type lysosomal storage disease.
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Lee J, Kim M, Itoh TQ, Lim C. Ataxin-2: A versatile posttranscriptional regulator and its implication in neural function. WILEY INTERDISCIPLINARY REVIEWS-RNA 2018; 9:e1488. [PMID: 29869836 DOI: 10.1002/wrna.1488] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 05/04/2018] [Accepted: 05/09/2018] [Indexed: 12/13/2022]
Abstract
Ataxin-2 (ATXN2) is a eukaryotic RNA-binding protein that is conserved from yeast to human. Genetic expansion of a poly-glutamine tract in human ATXN2 has been implicated in several neurodegenerative diseases, likely acting through gain-of-function effects. Emerging evidence, however, suggests that ATXN2 plays more direct roles in neural function via specific molecular and cellular pathways. ATXN2 and its associated protein complex control distinct steps in posttranscriptional gene expression, including poly-A tailing, RNA stabilization, microRNA-dependent gene silencing, and translational activation. Specific RNA substrates have been identified for the functions of ATXN2 in aspects of neural physiology, such as circadian rhythms and olfactory habituation. Genetic models of ATXN2 loss-of-function have further revealed its significance in stress-induced cytoplasmic granules, mechanistic target of rapamycin signaling, and cellular metabolism, all of which are crucial for neural homeostasis. Accordingly, we propose that molecular evolution has been selecting the ATXN2 protein complex as an important trans-acting module for the posttranscriptional control of diverse neural functions. This explains how ATXN2 intimately interacts with various neurodegenerative disease genes, and suggests that loss-of-function effects of ATXN2 could be therapeutic targets for ATXN2-related neurological disorders. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Affiliation(s)
- Jongbo Lee
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea
| | - Minjong Kim
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea
| | - Taichi Q Itoh
- Faculty of Arts and Science, Kyushu University, Fukuoka, Japan
| | - Chunghun Lim
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea
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Squadrone S, Brizio P, Mancini C, Abete MC, Brusco A. Altered homeostasis of trace elements in the blood of SCA2 patients. J Trace Elem Med Biol 2018; 47:111-114. [PMID: 29544796 DOI: 10.1016/j.jtemb.2018.02.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 02/06/2018] [Accepted: 02/08/2018] [Indexed: 01/03/2023]
Abstract
Spinocerebellar ataxia type 2 (SCA2) is a neurological disorder characterized by cerebellar dysfunction. The possible association between metals and neurodegenerative diseases is under constant investigation, with particular focus on their involvement in oxidative stress and their potential role as biomarkers of these pathologies. Whole blood samples of SCA2 patients and of healthy individuals were subjected to multi-elemental analysis by inductively coupled plasma-mass spectrometry (ICP-MS). Reduced levels of manganese and copper were found in SCA2 patients, while zinc and vanadium concentrations were significantly higher in patients compared to controls. Copper, manganese and zinc are cofactors of many enzymes (such as superoxide dismutase, SOD) involved in the cellular antioxidant response, whereas vanadium is a transition metal able to produce reactive radicals. A marked decrease of the antioxidant response has been previously reported in SCA2 patients. We suggest that an unbalance of transitional elements in the blood may reflect altered antioxidant homeostasis in SCA2 patients and could constitute a future peripheral biomarker for this disease. In addition, we suggest a possible role of vanadium in the altered lipid metabolism of SCA2 patients.
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Affiliation(s)
- Stefania Squadrone
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, via Bologna 148, 10154 Torino, Italy.
| | - Paola Brizio
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, via Bologna 148, 10154 Torino, Italy
| | - Cecilia Mancini
- University of Torino, Department of Medical Sciences, 10126 Torino, Italy
| | - Maria Cesarina Abete
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, via Bologna 148, 10154 Torino, Italy
| | - Alfredo Brusco
- University of Torino, Department of Medical Sciences, 10126 Torino, Italy; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, 10126 Torino, Italy
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Scoles DR, Pulst SM. Spinocerebellar Ataxia Type 2. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1049:175-195. [PMID: 29427103 DOI: 10.1007/978-3-319-71779-1_8] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Spinocerebellar ataxia type 2 (SCA2) is autosomal dominantly inherited and caused by CAG repeat expansion in the ATXN2 gene. Because the CAG repeat expansion is localized to an encoded region of ATXN2, the result is an expanded polyglutamine (polyQ) tract in the ATXN2 protein. SCA2 is characterized by progressive ataxia, and slow saccades. No treatment for SCA2 exists. ATXN2 mutation causes gains of new or toxic functions for the ATXN2 protein, resulting in abnormally slow Purkinje cell (PC) firing frequency and ultimately PC loss. This chapter describes the characteristics of SCA2 patients briefly, and reviews ATXN2 molecular features and progress toward the identification of a treatment for SCA2.
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Affiliation(s)
- Daniel R Scoles
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT, 84132, USA
| | - Stefan M Pulst
- Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT, 84132, USA.
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50
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Halbach MV, Gispert S, Stehning T, Damrath E, Walter M, Auburger G. Atxn2 Knockout and CAG42-Knock-in Cerebellum Shows Similarly Dysregulated Expression in Calcium Homeostasis Pathway. THE CEREBELLUM 2017; 16:68-81. [PMID: 26868665 PMCID: PMC5243904 DOI: 10.1007/s12311-016-0762-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disorder with preferential affection of Purkinje neurons, which are known as integrators of calcium currents. The expansion of a polyglutamine (polyQ) domain in the RNA-binding protein ataxin-2 (ATXN2) is responsible for this disease, but the causal roles of deficient ATXN2 functions versus aggregation toxicity are still under debate. Here, we studied mouse mutants with Atxn2 knockout (KO) regarding their cerebellar global transcriptome by microarray and RT-qPCR, in comparison with data from Atxn2-CAG42-knock-in (KIN) mouse cerebellum. Global expression downregulations involved lipid and growth signaling pathways in good agreement with previous data. As a novel effect, downregulations of key factors in calcium homeostasis pathways (the transcription factor Rora, transporters Itpr1 and Atp2a2, as well as regulator Inpp5a) were observed in the KO cerebellum, and some of them also occurred subtly early in KIN cerebellum. The ITPR1 protein levels were depleted from soluble fractions of cerebellum in both mutants, but accumulated in its membrane-associated form only in the SCA2 model. Coimmunoprecipitation demonstrated no association of ITPR1 with Q42-expanded or with wild-type ATXN2. These findings provide evidence that the physiological functions and protein interactions of ATXN2 are relevant for calcium-mediated excitation of Purkinje cells as well as for ATXN2-triggered neurotoxicity. These insights may help to understand pathogenesis and tissue specificity in SCA2 and other polyQ ataxias like SCA1, where inositol regulation of calcium flux and RORalpha play a role.
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Affiliation(s)
- Melanie Vanessa Halbach
- Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany
| | - Suzana Gispert
- Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany
| | - Tanja Stehning
- Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany
| | - Ewa Damrath
- Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany
| | - Michael Walter
- Institute for Medical Genetics, Eberhard-Karls-University of Tuebingen, 72076, Tuebingen, Germany
| | - Georg Auburger
- Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
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