|
1
|
Ashitomi H, Nakagawa T, Nakagawa M, Hosoi T. Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders. Biomedicines 2025; 13:810. [PMID: 40299365 PMCID: PMC12024872 DOI: 10.3390/biomedicines13040810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/30/2025] Open
Abstract
Ubiquitination is a dynamic and tightly regulated post-translational modification essential for modulating protein stability, trafficking, and function to preserve cellular homeostasis. This process is orchestrated through a hierarchical enzymatic cascade involving three key enzymes: the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, and the E3 ubiquitin ligase. The final step of ubiquitination is catalyzed by the E3 ubiquitin ligase, which facilitates the transfer of ubiquitin from the E2 enzyme to the substrate, thereby dictating which proteins undergo ubiquitination. Emerging evidence underscores the critical roles of ubiquitin ligases in neurodevelopment, regulating fundamental processes such as neuronal polarization, axonal outgrowth, synaptogenesis, and synaptic function. Mutations in genes encoding ubiquitin ligases and the consequent dysregulation of these pathways have been increasingly implicated in a spectrum of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and attention-deficit/hyperactivity disorder. This review synthesizes current knowledge on the molecular mechanisms underlying neurodevelopment regulated by Cullin-RING ubiquitin ligases-the largest subclass of ubiquitin ligases-and their involvement in the pathophysiology of neurodevelopmental disorders. A deeper understanding of these mechanisms holds significant promise for informing novel therapeutic strategies, ultimately advancing clinical outcomes for individuals affected by neurodevelopmental disorders.
Collapse
Affiliation(s)
- Honoka Ashitomi
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0084, Japan; (H.A.)
| | - Tadashi Nakagawa
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0084, Japan; (H.A.)
- Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Makiko Nakagawa
- Institute of Gene Research, Yamaguchi University Science Research Center, Ube 755-8505, Japan
- Advanced Technology Institute, Life Science Division, Yamaguchi University, Ube 755-8611, Japan
| | - Toru Hosoi
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0084, Japan; (H.A.)
| |
Collapse
|
|
2
|
Sharma AR, Batra G, Dhir N, Jain A, Modi T, Saini L, Thakur N, Mishra A, Singh RS, Singh A, Singla R, Prakash A, Goyal M, Bhatia A, Medhi B, Modi M. "Comparative evaluation of different chemical agents induced Autism Spectrum Disorder in experimental Wistar rats". Behav Brain Res 2024; 458:114728. [PMID: 37923221 DOI: 10.1016/j.bbr.2023.114728] [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: 07/30/2023] [Revised: 10/04/2023] [Accepted: 10/18/2023] [Indexed: 11/07/2023]
Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with uncertain etiology and pathophysiology. Several studies revealed that the commonly used animal models like Valproic Acid (VPA) and Propionic Acid (PPA) do not precisely represent the disease as the human patient does. The current study was conducted on different chemically (VPA, PPA, Poly I:C, Dioxin (2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)) & Chlorpyrifos (CPF)) induced ASD-like animal models and validated the best suitable experimental animal model, which would closely resemble with clinical features of the ASD. This validated model might help to explore the pathophysiology of ASD. This study included rat pups prenatally exposed to VPA, PPA, Poly I:C, Dioxin & CPF within GD9 to GD15 doses. The model groups were validated through developmental and behavioral parameters, Gene Expressions, Oxidative Stress, and Pro-inflammatory and Anti-inflammatory cytokines levels. Developmental and neurobehavioral parameters showed significant changes in model groups compared to the control. In oxidative stress parameters and neuro-inflammatory cytokines levels, model groups exhibited high oxidative stress and neuro-inflammation compared to control groups. Gene expression profile of ASD-related genes showed significant downregulation in model groups compared to the control group. Moreover, the Poly I:C group showed more significant results than other model groups. The comparison of available ASD-like experimental animal models showed that the Poly I:C induced model represented the exact pathophysiology of ASD as the human patient does. Poly I:C was reported in the maternal immune system activation via the inflammatory cytokines pathway, altering embryonic development and causing ASD in neonates.
Collapse
Affiliation(s)
- Amit Raj Sharma
- Department of Neurology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Gitika Batra
- Department of Neurology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Neha Dhir
- Department of Pharmacology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Ashish Jain
- Department of Pharmacology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Tanish Modi
- Clinical Trainee, Department of Neurology, PGIMER, Chandigarh, India
| | - Lokesh Saini
- All India Institute of Medical Sciences, Paediatric Neurology, Jodhpur, India
| | - Neetika Thakur
- Department of Endocrinology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Abhishek Mishra
- University of Minnesota Twin Cities, Department of Biomedical Sciences, USA
| | - Rahul Solomon Singh
- Department of Pharmacology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Ashutosh Singh
- Department of Pharmacology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Rubal Singla
- University of Minnesota Twin Cities, Department of Biomedical Sciences, USA
| | - Ajay Prakash
- Department of Pharmacology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Manoj Goyal
- Department of Neurology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Bikash Medhi
- Department of Pharmacology, Post Graduate Institute Medical Education and Research, Chandigarh, India
| | - Manish Modi
- Department of Neurology, Post Graduate Institute Medical Education and Research, Chandigarh, India.
| |
Collapse
|
|
3
|
Prince N, Chu SH, Chen Y, Mendez KM, Hanson E, Green-Snyder L, Brooks E, Korrick S, Lasky-Su JA, Kelly RS. Phenotypically driven subgroups of ASD display distinct metabolomic profiles. Brain Behav Immun 2023; 111:21-29. [PMID: 37004757 PMCID: PMC11099628 DOI: 10.1016/j.bbi.2023.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/08/2023] [Accepted: 03/28/2023] [Indexed: 04/04/2023] Open
Abstract
Autism Spectrum Disorder (ASD) is a heterogeneous condition that includes a broad range of characteristics and associated comorbidities; however, the biology underlying the variability in phenotypes is not well understood. As ASD impacts approximately 1 in 100 children globally, there is an urgent need to better understand the biological mechanisms that contribute to features of ASD. In this study, we leveraged rich phenotypic and diagnostic information related to ASD in 2001 individuals aged 4 to 17 years from the Simons Simplex Collection to derive phenotypically driven subgroups and investigate their respective metabolomes. We performed hierarchical clustering on 40 phenotypes spanning four ASD clinical domains, resulting in three subgroups with distinct phenotype patterns. Using global plasma metabolomic profiling generated by ultrahigh-performance liquid chromatography mass spectrometry, we characterized the metabolome of individuals in each subgroup to interrogate underlying biology related to the subgroups. Subgroup 1 included children with the least maladaptive behavioral traits (N = 862); global decreases in lipid metabolites and concomitant increases in amino acid and nucleotide pathways were observed for children in this subgroup. Subgroup 2 included children with the highest degree of challenges across all phenotype domains (N = 631), and their metabolome profiles demonstrated aberrant metabolism of membrane lipids and increases in lipid oxidation products. Subgroup 3 included children with maladaptive behaviors and co-occurring conditions that showed the highest IQ scores (N = 508); these individuals had increases in sphingolipid metabolites and fatty acid byproducts. Overall, these findings indicated distinct metabolic patterns within ASD subgroups, which may reflect the biological mechanisms giving rise to specific patterns of ASD characteristics. Our results may have important clinical applications relevant to personalized medicine approaches towards managing ASD symptoms.
Collapse
Affiliation(s)
- Nicole Prince
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Su H Chu
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Yulu Chen
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Kevin M Mendez
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ellen Hanson
- Divisions of Neurology and Developmental Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | | | | | - Susan Korrick
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jessica A Lasky-Su
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Rachel S Kelly
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
4
|
Perineuronal Nets in the Dorsomedial Striatum Contribute to Behavioral Dysfunction in Mouse Models of Excessive Repetitive Behavior. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2022; 2:460-469. [PMID: 36324654 PMCID: PMC9616293 DOI: 10.1016/j.bpsgos.2021.11.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/29/2021] [Accepted: 11/03/2021] [Indexed: 11/25/2022] Open
Abstract
Background Excessive repetitive behavior is a debilitating symptom of several neuropsychiatric disorders. Parvalbumin-positive inhibitory interneurons in the dorsal striatum have been linked to repetitive behavior, and a sizable portion of these cells are surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures. Although PNNs have been associated with plasticity and neuropsychiatric disease, no previous studies have investigated their involvement in excessive repetitive behavior. Methods We used histochemistry and confocal imaging to investigate PNNs surrounding parvalbumin-positive cells in the dorsal striatum of 4 mouse models of excessive repetitive behavior (BTBR, Cntnap2, Shank3, prenatal valproate treatment). We then investigated one of these models, the BTBR mouse, in detail, with DiI labeling, in vivo and in vitro recordings, and behavioral analyses. We next degraded PNNs in the dorsomedial striatum (DMS) using the enzyme chondroitinase ABC and assessed dendritic spine density, electrophysiology, and repetitive behavior. Results We found a greater percentage of parvalbumin-positive interneurons with PNNs in the DMS of all 4 mouse models of excessive repetitive behavior compared with control mice. In BTBR mice, we found fewer dendritic spines on medium spiny neurons (targets of parvalbumin-positive interneurons) and differences in neuronal oscillations as well as inhibitory postsynaptic potentials compared with control mice. Reduction of DMS PNNs in BTBR mice altered dendritic spine density and inhibitory responses and normalized repetitive behavior. Conclusions These findings suggest that cellular abnormalities in the DMS are associated with maladaptive repetitive behaviors and that manipulating PNNs can restore normal levels of repetitive behavior while altering DMS dendritic spines and inhibitory signaling.
Collapse
|
|
5
|
Su Y, Yang X, Yang L, Liu X, She Z, Zhang Y, Dong Z. Thyroid hormones regulate reelin expression in neuropsychiatric disorders. Can J Physiol Pharmacol 2022; 100:1033-1044. [PMID: 36166833 DOI: 10.1139/cjpp-2022-0270] [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: 11/22/2022]
Abstract
The incidence and prevalence of hypothyroidism in pregnancy have increased over the past two decades, leading to the occurrence of neuropsychiatric disorders. However, the underlying mechanisms of thyroid hormone (TH)-regulated gene expression and neuropsychiatric development during the postnatal period remain unknown. Recent achievements have shown that reelin, a large extracellular glycoprotein, plays a crucial role in neuronal migration and localization during the development of neocortex and cerebellar cortex, thereby participating in the development of neuropsychiatric diseases. Reelin-induced neuronal migration requires triiodothyronine (T3) from the deiodination of thyroxine (T4) by fetal brain deiodinases. Previous studies have reported decreased reelin levels and abnormal gene expression, which are the same as the pathological alternations in reelin-induced neuropsychiatric disorders including schizophrenia and autism. Low T3 in the fetal brain due to hypothyroxinemia during pregnancy may be detrimental to neuronal migration, leading to neuropsychiatric disorders. In this review, we focus on the reelin expression between hypothyroidism and neuropsychiatric disorders.
Collapse
Affiliation(s)
- Yadi Su
- College of Stomatology, Chongqing Medical University, Chongqing, 401334, PR China
| | - Xiaoyu Yang
- College of Pediatrics, Chongqing Medical University, Chongqing, 401334, PR China
| | - Lu Yang
- College of Stomatology, Chongqing Medical University, Chongqing, 401334, PR China
| | - Xinjing Liu
- College of Public Health and Management, Chongqing Medical University, Chongqing, 401334, PR China
| | - Zhenghang She
- College of Pediatrics, Chongqing Medical University, Chongqing, 401334, PR China
| | - Youwen Zhang
- College of Pediatrics, Chongqing Medical University, Chongqing, 401334, PR China
| | - Zhifang Dong
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China
| |
Collapse
|
|
6
|
Fair SR, Schwind W, Julian DL, Biel A, Guo G, Rutherford R, Ramadesikan S, Westfall J, Miller KE, Kararoudi MN, Hickey SE, Mosher TM, McBride KL, Neinast R, Fitch J, Lee DA, White P, Wilson RK, Bedrosian TA, Koboldt DC, Hester ME. Cerebral organoids containing an AUTS2 missense variant model microcephaly. Brain 2022; 146:387-404. [PMID: 35802027 PMCID: PMC9825673 DOI: 10.1093/brain/awac244] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 05/22/2022] [Accepted: 06/22/2022] [Indexed: 01/12/2023] Open
Abstract
Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control cerebral organoids. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-catenin signalling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of cerebral organoids to investigate molecular mechanisms underlying AUTS2 syndrome.
Collapse
Affiliation(s)
- Summer R Fair
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Wesley Schwind
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Dominic L Julian
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Alecia Biel
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Gongbo Guo
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Ryan Rutherford
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Swetha Ramadesikan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Jesse Westfall
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Katherine E Miller
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Meisam Naeimi Kararoudi
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Scott E Hickey
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA,Division of Genetic and Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Theresa Mihalic Mosher
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Kim L McBride
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA,Division of Genetic and Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA,Center for Cardiovascular Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Reid Neinast
- Center for Cardiovascular Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - James Fitch
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Dean A Lee
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Peter White
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Richard K Wilson
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Tracy A Bedrosian
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Daniel C Koboldt
- Correspondence may also be addressed to: Daniel C. Koboldt, MS E-mail:
| | - Mark E Hester
- Correspondence to: Mark E. Hester, PhD 575 Children’s Crossroad Columbus OH 43205-2716, USA E-mail:
| |
Collapse
|
|
7
|
Priyadarshi S, Hansdah K, Singh N, Bouzid A, Ray CS, Panda KC, Biswal NC, Desai A, Choudhury JC, Tekari A, Masmoudi S, Ramchander PV. The risks of RELN polymorphisms and its expression in the development of otosclerosis. PLoS One 2022; 17:e0269558. [PMID: 35658052 PMCID: PMC9165908 DOI: 10.1371/journal.pone.0269558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 05/23/2022] [Indexed: 11/19/2022] Open
Abstract
Otosclerosis (OTSC) is the primary form of conductive hearing loss characterized by abnormal bone remodelling within the otic capsule of the human middle ear. A genetic association of the RELN SNP rs3914132 with OTSC has been identified in European population. Previously, we showed a trend towards association of this polymorphism with OTSC and identified a rare variant rs74503667 in a familial case. Here, we genotyped these variants in an Indian cohort composed of 254 OTSC cases and 262 controls. We detected a significant association of rs3914132 with OTSC (OR = 0.569, 95%CI = 0.386–0.838, p = 0.0041). To confirm this finding, we completed a meta-analysis which revealed a significant association of the rs3914132 polymorphism with OTSC (Z = 6.707, p<0.0001) across different ethnic populations. Linkage analysis found the evidence of linkage at RELN locus (LOD score 2.1059) in the OTSC family which has shown the transmission of rare variant rs74503667 in the affected individuals. To understand the role of RELN and its receptors in the development of OTSC, we went further to perform a functional analysis of RELN/reelin. Here we detected a reduced RELN (p = 0.0068) and VLDLR (p = 0.0348) mRNA levels in the otosclerotic stapes tissues. Furthermore, a reduced reelin protein expression by immunohistochemistry was confirmed in the otosclerotic tissues. Electrophoretic mobility shift assays for rs3914132 and rs74503667 variants revealed an altered binding of transcription factors in the mutated sequences which indicates the regulatory role of these variations in the RELN gene regulation. Subsequently, we showed by scanning electron microscopy a change in stapes bone morphology of otosclerotic patients. In conclusion, this study evidenced that the rare variation rs74503667 and the common polymorphism rs3914132 in the RELN gene and its reduced expressions that were associated with OTSC.
Collapse
Affiliation(s)
- Saurabh Priyadarshi
- Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, India
| | - Kirtal Hansdah
- Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, India
| | - Neha Singh
- Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, India
| | - Amal Bouzid
- Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Chinmay Sundar Ray
- Department of Ear, Nose, and Throat (ENT), Shrirama Chandra Bhanj (SCB) Medical College & Hospital, Cuttack, India
| | | | - Narayan Chandra Biswal
- Department of Ear, Nose, and Throat (ENT), Shrirama Chandra Bhanj (SCB) Medical College & Hospital, Cuttack, India
| | - Ashim Desai
- Dr. ABR Desai Ear, Nose and Throat (ENT) Clinic and Research Centre, Mumbai, India
| | - Jyotish Chandra Choudhury
- Department of Forensic Medicine & Toxicology (FMT), Shrirama Chandra Bhanj (SCB) Medical College & Hospital, Cuttack, India
| | - Adel Tekari
- Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Saber Masmoudi
- Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | | |
Collapse
|
|
8
|
Iyshwarya B, Vajagathali M, Ramakrishnan V. Investigation of Genetic Polymorphism in Autism Spectrum Disorder: a Pathogenesis of the Neurodevelopmental Disorder. ADVANCES IN NEURODEVELOPMENTAL DISORDERS 2022; 6:136-146. [DOI: 10.1007/s41252-022-00251-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/12/2022] [Indexed: 12/07/2023]
|
|
9
|
Scala M, Grasso EA, Di Cara G, Riva A, Striano P, Verrotti A. The Pathophysiological Link Between Reelin and Autism: Overview and New Insights. Front Genet 2022; 13:869002. [PMID: 35422848 PMCID: PMC9002092 DOI: 10.3389/fgene.2022.869002] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Reelin is a secreted extracellular matrix protein playing pivotal roles in neuronal migration and cortical stratification during embryonal brain development. In the adult brain, its activity is crucial for synaptic plasticity, memory processing, and cognition. Genetic alterations in RELN have been variably reported as possible contributors to the pathogenesis of autism spectrum disorders (ASD). In particular, GCCs repeats in the 5′UTR, and single nucleotide polymorphysms (SNPs) in RELN have been suggested to affect brain development and predispose to autism. We reviewed pertinent literature on RELN expression and haplotypes transmission in children with ASD, critically analyzing available evidence in support of the pathophysiological association between Reelin deficiency and ASD.
Collapse
Affiliation(s)
- Marcello Scala
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal, and Child Health (DINOGMI), University of Genoa, Genoa, Italy.,Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, University of Genoa, Genoa, Italy
| | | | - Giuseppe Di Cara
- Department of Medicine and Surgery, Pediatric Clinic, University of Perugia, Perugia, Italy
| | - Antonella Riva
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal, and Child Health (DINOGMI), University of Genoa, Genoa, Italy.,Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, University of Genoa, Genoa, Italy
| | - Pasquale Striano
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal, and Child Health (DINOGMI), University of Genoa, Genoa, Italy.,Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, University of Genoa, Genoa, Italy
| | - Alberto Verrotti
- Department of Medicine and Surgery, Pediatric Clinic, University of Perugia, Perugia, Italy
| |
Collapse
|
|
10
|
Rodriguez-Gomez DA, Garcia-Guaqueta DP, Charry-Sánchez JD, Sarquis-Buitrago E, Blanco M, Velez-van-Meerbeke A, Talero-Gutiérrez C. A systematic review of common genetic variation and biological pathways in autism spectrum disorder. BMC Neurosci 2021; 22:60. [PMID: 34627165 PMCID: PMC8501721 DOI: 10.1186/s12868-021-00662-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/16/2021] [Indexed: 01/21/2023] Open
Abstract
Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and interaction. Common genetic variation appears to play a key role in the development of this condition. In this systematic review, we describe the relationship between genetic variations and autism. We created a gene dataset of the genes involved in the pathogenesis of autism and performed an over-representation analysis to evaluate the biological functions and molecular pathways that may explain the associations between these variants and the development of ASD. Results 177 studies and a gene set composed of 139 were included in this qualitative systematic review. Enriched pathways in the over-representation analysis using the KEGG pathway database were mostly associated with neurotransmitter receptors and their subunits. Major over-represented biological processes were social behavior, vocalization behavior, learning and memory. The enriched cellular component of the proteins encoded by the genes identified in this systematic review were the postsynaptic membrane and the cell junction. Conclusions Among the biological processes that were examined, genes involved in synaptic integrity, neurotransmitter metabolism, and cell adhesion molecules were significantly involved in the development of autism. Supplementary Information The online version contains supplementary material available at 10.1186/s12868-021-00662-z.
Collapse
Affiliation(s)
- Diego Alejandro Rodriguez-Gomez
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia
| | - Danna Paola Garcia-Guaqueta
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia
| | - Jesús David Charry-Sánchez
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia
| | - Elias Sarquis-Buitrago
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia
| | - Mariana Blanco
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia
| | - Alberto Velez-van-Meerbeke
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia.,NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia
| | - Claudia Talero-Gutiérrez
- Neuroscience Research Group (NeURos), NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia. .,NeuroVitae Center for Neuroscience, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 111221, Bogotá D.C., Colombia.
| |
Collapse
|
|
11
|
Ahmed S, Rakib A, Uddin MMN, Islam MS, Ullah SA, Emran TB. Association of reelin gene (RELN) polymorphism with autism spectrum disorder in the Bangladeshi population. Meta Gene 2021; 29:100901. [DOI: 10.1016/j.mgene.2021.100901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
|
|
12
|
5-Aminoisoquinolinone, a PARP-1 Inhibitor, Ameliorates Immune Abnormalities through Upregulation of Anti-Inflammatory and Downregulation of Inflammatory Parameters in T Cells of BTBR Mouse Model of Autism. Brain Sci 2021; 11:brainsci11020249. [PMID: 33671196 PMCID: PMC7922312 DOI: 10.3390/brainsci11020249] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/19/2021] [Accepted: 02/13/2021] [Indexed: 12/02/2022] Open
Abstract
Autism spectrum disorder (ASD) covers a range of neurodevelopmental disorders involving impairments in communication and repetitive and stereotyped patterns of behavior and reciprocal social interaction. 5-Aminoisoquinolinone (5-AIQ), a PARP-1 inhibitor, has neuroprotective and anti-inflammatory effects. We investigated the influence of 5-AIQ-treatment in BTBR T+ Itpr3tf/J (BTBR) mice as an autism model and used flow cytometry to assess the effect of 5-AIQ on FOXP3, Helios, GATA3, IL-9, IL-10 and IL-17A production by CXCR6+ and CD4+ T cells in the spleen. We also confirmed the effect of 5-AIQ treatment on expression of FOXP3, Helios, GATA3, IL-17A, IL-10, and IL-9 mRNA and protein expression levels in the brain tissue by quantitative PCR and western blotting. Our results demonstrated that 5-AIQ-treated BTBR mice had significantly increased numbers of CXCR6+FOXP3+, CXCR6+IL-10+, and CXCR6+Helios+ cells and decreased numbers of CD4+GATA3+, CD4+IL-9+, and CD4+IL-17A+ cells as compared with those in untreated BTBR mice. Our results further demonstrated that treatment with 5-AIQ in BTBR mice increased expression for FOXP3, IL-10, and Helios, and decreased expression for GATA3, IL-17A, and IL-9 mRNA. Our findings support the hypotheses that 5-AIQ has promising novel therapeutic effects on neuroimmune dysfunction in autism and is associated with modulation of Treg and Th17 cells.
Collapse
|
|
13
|
Guan J, Lin Y, Wang Y, Gao J, Ji G. An analytical method for the identification of cell type-specific disease gene modules. J Transl Med 2021; 19:20. [PMID: 33407556 PMCID: PMC7788893 DOI: 10.1186/s12967-020-02690-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
Background Genome-wide association studies have identified genetic variants associated with the risk of brain-related diseases, such as neurological and psychiatric disorders, while the causal variants and the specific vulnerable cell types are often needed to be studied. Many disease-associated genes are expressed in multiple cell types of human brains, while the pathologic variants affect primarily specific cell types. We hypothesize a model in which what determines the manifestation of a disease in a cell type is the presence of disease module comprised of disease-associated genes, instead of individual genes. Therefore, it is essential to identify the presence/absence of disease gene modules in cells. Methods To characterize the cell type-specificity of brain-related diseases, we construct human brain cell type-specific gene interaction networks integrating human brain nucleus gene expression data with a referenced tissue-specific gene interaction network. Then from the cell type-specific gene interaction networks, we identify significant cell type-specific disease gene modules by performing statistical tests. Results Between neurons and glia cells, the constructed cell type-specific gene networks and their gene functions are distinct. Then we identify cell type-specific disease gene modules associated with autism spectrum disorder and find that different gene modules are formed and distinct gene functions may be dysregulated in different cells. We also study the similarity and dissimilarity in cell type-specific disease gene modules among autism spectrum disorder, schizophrenia and bipolar disorder. The functions of neurons-specific disease gene modules are associated with synapse for all three diseases, while those in glia cells are different. To facilitate the use of our method, we develop an R package, CtsDGM, for the identification of cell type-specific disease gene modules. Conclusions The results support our hypothesis that a disease manifests itself in a cell type through forming a statistically significant disease gene module. The identification of cell type-specific disease gene modules can promote the development of more targeted biomarkers and treatments for the disease. Our method can be applied for depicting the cell type heterogeneity of a given disease, and also for studying the similarity and dissimilarity between different disorders, providing new insights into the molecular mechanisms underlying the pathogenesis and progression of diseases.
Collapse
Affiliation(s)
- Jinting Guan
- Department of Automation, Xiamen University, Xiamen, China. .,National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, China.
| | - Yiping Lin
- Department of Automation, Xiamen University, Xiamen, China
| | - Yang Wang
- Department of Automation, Xiamen University, Xiamen, China
| | - Junchao Gao
- Department of Instrumental and Electrical Engineering, Xiamen University, Xiamen, China
| | - Guoli Ji
- Department of Automation, Xiamen University, Xiamen, China.,National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, China.,Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, China
| |
Collapse
|
|
14
|
Uddin MG, Siddiqui SA, Uddin MS, Aziz MA, Hussain MS, Furhatun-Noor, Millat MS, Sen N, Muhuri B, Islam MS. Genetic variants of ZNF385B and COMT are associated with autism spectrum disorder in the Bangladeshi children. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100820] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
|
|
15
|
Philippot G, Hellsten SV, Viberg H, Fredriksson R. Evaluation of the dentate gyrus in adult mice exposed to acetaminophen (paracetamol) on postnatal day 10. Int J Dev Neurosci 2020; 81:91-97. [PMID: 33222217 DOI: 10.1002/jdn.10079] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 11/16/2020] [Accepted: 11/16/2020] [Indexed: 11/09/2022] Open
Abstract
Acetaminophen (AAP; or paracetamol) is a widely used nonprescription drug with antipyretic and analgesic properties. Alarmingly, there is an increasing body of evidence showing that developmental exposure to AAP is associated with adverse behavioural outcomes later in life. We have previously shown that relevant doses of AAP in 10-day-old mice affected memory, learning and locomotor activity in the adult animals. Interestingly, the neurons of the dentate gyrus (DG) have a relatively late time of origin as they are generated during the first two weeks of postnatal life in rodents. Since the generation of these cells, which are important for memory processing, coincides with our AAP exposure, we aim to investigate if the cytoarchitecture of the DG is affected by postnatal day 10 AAP treatment. In addition, we investigate if markers for differentiation and migration in the hippocampus were affected by the same treatment. We did not observe any visual effects in adult DG cytoarchitecture, nor any changes of markers for differentiation/migration in the hippocampus in 24 hr after exposure. Even though a large effect size was estimated on adult DG thickness following AAP exposure, the estimated 95% CIs around the differences of the means reveal no significant effect. Hence, larger sample sizes are warranted to clarify if neonatal AAP exposure affects adult DG thickness in mice.
Collapse
Affiliation(s)
- Gaëtan Philippot
- Department of Pharmaceutical Biosciences, Molecular Neuropharmacology, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Sofie V Hellsten
- Department of Pharmaceutical Biosciences, Molecular Neuropharmacology, Biomedical Center, Uppsala University, Uppsala, Sweden
| | - Henrik Viberg
- Department of Organismal Biology, Environmental Toxicology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden
| | - Robert Fredriksson
- Department of Pharmaceutical Biosciences, Molecular Neuropharmacology, Biomedical Center, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
16
|
Hernández-García I, Chamorro AJ, Ternavasio-de la Vega HG, Carbonell C, Marcos M, Mirón-Canelo JA. Association of Allelic Variants of the Reelin Gene with Autistic Spectrum Disorder: A Systematic Review and Meta-Analysis of Candidate Gene Association Studies. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17218010. [PMID: 33143244 PMCID: PMC7663127 DOI: 10.3390/ijerph17218010] [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] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/20/2020] [Accepted: 10/28/2020] [Indexed: 01/15/2023]
Abstract
Autistic spectrum disorder (ASD) is a complex neurodevelopmental disability with a genetic basis, and several studies have suggested a potential role of the reelin gene (RELN) in ASD susceptibility. Accordingly, genetic association studies have explored this potential association, but the results have been controversial thus far. For this reason, we assessed the association of four genetic variants of RELN (the 5′UTR CGG triplet repeat and polymorphisms rs736707, rs362691, and rs2229864) with ASD by means of a systematic review and meta-analysis. We retrieved studies comparing the distribution of the above-mentioned genetic variants between ASD patients and healthy controls. A meta-analysis was conducted using a random effects model, and calculations of the odds ratios (ORs) and confidence intervals (CIs) were performed. A sensitivity analysis and tests to determine the heterogeneity of the results were also performed. Eleven previous studies fulfilled the inclusion criteria and analyzed the association of the above-mentioned genetic variants and ASD. We did not find any significant association between the allele or genotype frequencies of the analyzed polymorphisms and ASD, and large heterogeneity was found for the rs736707 polymorphism. Moreover, no significant differences were found between the 5′UTR triplet repeat and this disorder. In light of current evidence, no single genetic variant within this gene is clearly associated with the development of ASD, and ethnic differences may explain part of the observed heterogeneity. Larger studies among different ethnic groups are needed to establish the role of specific genetic variants within RELN in the etiology of this disorder.
Collapse
Affiliation(s)
- Ignacio Hernández-García
- Department of Preventive Medicine and Public Health, Lozano Blesa University Clinical Hospital of Zaragoza, Calle San Juan Bosco 15, 50009 Zaragoza, Spain
- Correspondence: ; Tel.: +34-976-765-700
| | - Antonio-Javier Chamorro
- Department of Medicine, University of Salamanca, 37007 Salamanca, Spain; (A.-J.C.); (H.G.T.-d.l.V.); (C.C.); (M.M.)
- Department of Internal Medicine, University Hospital of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Hugo Guillermo Ternavasio-de la Vega
- Department of Medicine, University of Salamanca, 37007 Salamanca, Spain; (A.-J.C.); (H.G.T.-d.l.V.); (C.C.); (M.M.)
- Department of Internal Medicine, University Hospital of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Cristina Carbonell
- Department of Medicine, University of Salamanca, 37007 Salamanca, Spain; (A.-J.C.); (H.G.T.-d.l.V.); (C.C.); (M.M.)
- Department of Internal Medicine, University Hospital of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Miguel Marcos
- Department of Medicine, University of Salamanca, 37007 Salamanca, Spain; (A.-J.C.); (H.G.T.-d.l.V.); (C.C.); (M.M.)
- Department of Internal Medicine, University Hospital of Salamanca, 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - José-Antonio Mirón-Canelo
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
- Department of Epidemiology, University of Salamanca, 37007 Salamanca, Spain
| |
Collapse
|
|
17
|
Genetic Variation and Autism: A Field Synopsis and Systematic Meta-Analysis. Brain Sci 2020; 10:brainsci10100692. [PMID: 33007889 PMCID: PMC7600188 DOI: 10.3390/brainsci10100692] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/13/2020] [Accepted: 09/14/2020] [Indexed: 12/16/2022] Open
Abstract
This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.
Collapse
|
|
18
|
Jossin Y. Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation. Biomolecules 2020; 10:biom10060964. [PMID: 32604886 PMCID: PMC7355739 DOI: 10.3390/biom10060964] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/14/2022] Open
Abstract
During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders.
Collapse
Affiliation(s)
- Yves Jossin
- Laboratory of Mammalian Development & Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, 1200 Brussels, Belgium
| |
Collapse
|
|
19
|
Yoon SH, Choi J, Lee WJ, Do JT. Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder. J Clin Med 2020; 9:E966. [PMID: 32244359 PMCID: PMC7230567 DOI: 10.3390/jcm9040966] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/28/2020] [Accepted: 03/28/2020] [Indexed: 12/19/2022] Open
Abstract
Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities and interests. Environmental factors, such as viral infection, parental age, and zinc deficiency, can be plausible contributors to ASD susceptibility. As ASD is highly heritable, genetic risk factors involved in neurodevelopment, neural communication, and social interaction provide important clues in explaining the etiology of ASD. Accumulated evidence also shows an important role of epigenetic factors, such as DNA methylation, histone modification, and noncoding RNA, in ASD etiology. In this review, we compiled the research published to date and described the genetic and epigenetic epidemiology together with environmental risk factors underlying the etiology of the different phenotypes of ASD.
Collapse
Affiliation(s)
| | | | | | - Jeong Tae Do
- Department of Stem Cell and Regenerative Biotechnology, KU Institute of Technology, Konkuk University, Seoul 05029, Korea; (S.H.Y.); (J.C.); (W.J.L.)
| |
Collapse
|
|
20
|
Möhrle D, Fernández M, Peñagarikano O, Frick A, Allman B, Schmid S. What we can learn from a genetic rodent model about autism. Neurosci Biobehav Rev 2020; 109:29-53. [DOI: 10.1016/j.neubiorev.2019.12.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 10/28/2019] [Accepted: 12/10/2019] [Indexed: 12/15/2022]
|
|
21
|
Maussion G, Rocha C, Bernard G, Beitel LK, Durcan TM. Patient-Derived Stem Cells, Another in vitro Model, or the Missing Link Toward Novel Therapies for Autism Spectrum Disorders? Front Pediatr 2019; 7:225. [PMID: 31245336 PMCID: PMC6562499 DOI: 10.3389/fped.2019.00225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 05/20/2019] [Indexed: 12/28/2022] Open
Abstract
Autism Spectrum Disorders (ASDs) is a multigenic and multifactorial neurodevelopmental group of disorders diagnosed in early childhood, leading to deficits in social interaction, verbal and non-verbal communication and characterized by restricted and repetitive behaviors and interests. To date, genetic, descriptive and mechanistic aspects of the ASDs have been investigated using mouse models and post-mortem brain tissue. More recently, the technology to generate stem cells from patients' samples has brought a new avenue for modeling ASD through 2D and 3D neuronal models that are derived from a patient's own cells, with the goal of building new therapeutic strategies for treating ASDs. This review analyses how studies performed on mouse models and human samples can complement each other, advancing our current knowledge into the pathophysiology of the ASDs. Regardless of the genetic and phenotypic heterogeneities of ASDs, convergent information regarding the molecular and cellular mechanisms involved in these disorders can be extracted from these models. Thus, considering the complexities of these disorders, patient-derived models have immense potential to elucidate molecular deregulations that contributed to the different autistic phenotypes. Through these direct investigations with the human in vitro models, they offer the potential for opening new therapeutic avenues that can be translated into the clinic.
Collapse
Affiliation(s)
- Gilles Maussion
- Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
| | - Cecilia Rocha
- Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
| | - Geneviève Bernard
- Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, QC, Canada
- Division of Medical Genetics, Department of Internal Medicine, McGill University Health Center, Montreal, QC, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- MyeliNeuroGene Laboratory, Research Institute of the McGill University Health Center, Montreal, QC, Canada
| | - Lenore K. Beitel
- Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
| | - Thomas M. Durcan
- Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
| |
Collapse
|
|
22
|
Serati M, Delvecchio G, Orsenigo G, Mandolini GM, Lazzaretti M, Scola E, Triulzi F, Brambilla P. The Role of the Subplate in Schizophrenia and Autism: A Systematic Review. Neuroscience 2019; 408:58-67. [PMID: 30930130 DOI: 10.1016/j.neuroscience.2019.03.049] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 03/19/2019] [Accepted: 03/20/2019] [Indexed: 02/07/2023]
Abstract
The subplate (SP) represents a transitory cytoarchitectural fetal compartment containing most subcortical and cortico-cortical afferents, and has a fundamental role in the structural development of the healthy adult brain. There is evidence that schizophrenia and autism may be determined by developmental defects in the cortex or cortical circuitry during the earliest stages of pregnancy. This article provides an overview on fetal SP development, considering its role in schizophrenia and autism, as supported by a systematic review of the main databases. The SP has been described as a cortical amplifier with a role in the coordination of cortical activity, and sensitive growth and migration windows have crucial consequences with respect to cognitive functioning. Although there are not enough studies to draw final conclusions, improved knowledge of the SP's role in schizophrenia and autism spectrum disorders may help to elucidate and possibly prevent the onset of these two severe disorders.
Collapse
Affiliation(s)
- Marta Serati
- Department of Mental Health, ASST Rhodense, Rho, Milan, Italy.
| | - Giuseppe Delvecchio
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Giulia Orsenigo
- Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Gian Mario Mandolini
- Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Matteo Lazzaretti
- Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Elisa Scola
- Department of Neuroradiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Fabio Triulzi
- Department of Neuroradiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paolo Brambilla
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Psychiatry and Behavioural Neurosciences, University of Texas at Houston, TX, USA
| |
Collapse
|
|
23
|
Liu Q, Chen MX, Sun L, Wallis CU, Zhou JS, Ao LJ, Li Q, Sham PC. Rational use of mesenchymal stem cells in the treatment of autism spectrum disorders. World J Stem Cells 2019; 11:55-72. [PMID: 30842805 PMCID: PMC6397804 DOI: 10.4252/wjsc.v11.i2.55] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/30/2018] [Accepted: 01/23/2019] [Indexed: 02/06/2023] Open
Abstract
Autism and autism spectrum disorders (ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental influences. Although the pathophysiology underlying ASD is still unclear, recent evidence suggests that immune dysregulation and neuroinflammation play a role in the etiology of ASD. In particular, there is direct evidence supporting a role for maternal immune activation during prenatal life in neurodevelopmental conditions. Currently, the available options of behavioral therapies and pharmacological and supportive nutritional treatments in ASD are only symptomatic. Given the disturbing rise in the incidence of ASD, and the fact that there is no effective pharmacological therapy for ASD, there is an urgent need for new therapeutic options. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that make them relevant to several diseases associated with inflammation and tissue damage. The paracrine regenerative mechanisms of MSCs are also suggested to be therapeutically beneficial for ASD. Thus the underlying pathology in ASD, including immune system dysregulation and inflammation, represent potential targets for MSC therapy. This review will focus on immune dysfunction in the pathogenesis of ASD and will further discuss the therapeutic potential for MSCs in mediating ASD-related immunological disorders.
Collapse
Affiliation(s)
- Qiang Liu
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Mo-Xian Chen
- School of Rehabilitation, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Lin Sun
- Department of Psychology, Weifang Medical University, Weifang 261053, Shandong Province, China
| | - Chloe U Wallis
- Medical Sciences Division, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Jian-Song Zhou
- Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Li-Juan Ao
- School of Rehabilitation, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Qi Li
- Department of Psychiatry, the University of Hong Kong, Hong Kong, China
| | - Pak C Sham
- Department of Psychiatry, the University of Hong Kong, Hong Kong, China
- State Key Laboratory of Brain and Cognitive Sciences, Center for Genomic Sciences, the University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
24
|
Schroeder A, van den Buuse M, Hill RA. Reelin Haploinsufficiency and Late-Adolescent Corticosterone Treatment Induce Long-Lasting and Female-Specific Molecular Changes in the Dorsal Hippocampus. Brain Sci 2018; 8:brainsci8070118. [PMID: 29941797 PMCID: PMC6070826 DOI: 10.3390/brainsci8070118] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/20/2018] [Accepted: 06/22/2018] [Indexed: 12/24/2022] Open
Abstract
Reelin depletion and stress seem to affect similar pathways including GABAergic and glutamatergic signaling and both are implicated in psychiatric disorders in late adolescence/early adulthood. The interaction between reelin depletion and stress, however, remains unclear. To investigate this, male and female heterozygous reelin mice (HRM) and wildtype (WT) controls were treated with the stress hormone, corticosterone (CORT), during late adolescence to simulate chronic stress. Glucocorticoid receptors (GR), N-methyl-d-aspartate receptor (NMDAr) subunits, glutamic acid decarboxylase (GAD67) and parvalbumin (PV) were measured in the hippocampus and the prefrontal cortex (PFC) in adulthood. While no changes were seen in male mice, female HRM showed a significant reduction in GR expression in the dorsal hippocampus. In addition, CORT reduced GR levels as well as GluN2B and GluN2C subunits of NMDAr in the dorsal hippocampus in female mice only. CORT furthermore reduced GluN1 levels in the PFC of female mice. The combined effect of HRM and CORT treatment appeared to be additive in terms of GR expression in the dorsal hippocampus. Female-specific CORT-induced changes were associated with overall higher circulating CORT levels in female compared to male mice. This study shows differential effects of reelin depletion and CORT treatment on GR and NMDAr protein expression in male and female mice, suggesting that females are more susceptible to reelin haploinsufficiency as well as late-adolescent stress. These findings shed more light on female-specific vulnerability to stress and have implications for stress-associated mental illnesses with a female bias including anxiety and major depression.
Collapse
Affiliation(s)
- Anna Schroeder
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3052, Australia.
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton 3168, Australia.
| | - Maarten van den Buuse
- School of Psychology and Public Health, La Trobe University, Bundoora 3086 Australia.
- Department of Pharmacology, University of Melbourne, Parkville 3052, Australia.
- The College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville 4810, Australia.
| | - Rachel A Hill
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3052, Australia.
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton 3168, Australia.
| |
Collapse
|
|
25
|
The functions of Reelin in membrane trafficking and cytoskeletal dynamics: implications for neuronal migration, polarization and differentiation. Biochem J 2017; 474:3137-3165. [PMID: 28887403 DOI: 10.1042/bcj20160628] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 07/27/2017] [Accepted: 08/01/2017] [Indexed: 02/06/2023]
Abstract
Reelin is a large extracellular matrix protein with relevant roles in mammalian central nervous system including neurogenesis, neuronal polarization and migration during development; and synaptic plasticity with its implications in learning and memory, in the adult. Dysfunctions in reelin signaling are associated with brain lamination defects such as lissencephaly, but also with neuropsychiatric diseases like autism, schizophrenia and depression as well with neurodegeneration. Reelin signaling involves a core pathway that activates upon reelin binding to its receptors, particularly ApoER2 (apolipoprotein E receptor 2)/LRP8 (low-density lipoprotein receptor-related protein 8) and very low-density lipoprotein receptor, followed by Src/Fyn-mediated phosphorylation of the adaptor protein Dab1 (Disabled-1). Phosphorylated Dab1 (pDab1) is a hub in the signaling cascade, from which several other downstream pathways diverge reflecting the different roles of reelin. Many of these pathways affect the dynamics of the actin and microtubular cytoskeleton, as well as membrane trafficking through the regulation of the activity of small GTPases, including the Rho and Rap families and molecules involved in cell polarity. The complexity of reelin functions is reflected by the fact that, even now, the precise mode of action of this signaling cascade in vivo at the cellular and molecular levels remains unclear. This review addresses and discusses in detail the participation of reelin in the processes underlying neurogenesis, neuronal migration in the cerebral cortex and the hippocampus; and the polarization, differentiation and maturation processes that neurons experiment in order to be functional in the adult brain. In vivo and in vitro evidence is presented in order to facilitate a better understanding of this fascinating system.
Collapse
|
|
26
|
Reilly J, Gallagher L, Chen JL, Leader G, Shen S. Bio-collections in autism research. Mol Autism 2017; 8:34. [PMID: 28702161 PMCID: PMC5504648 DOI: 10.1186/s13229-017-0154-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 06/23/2017] [Indexed: 01/06/2023] Open
Abstract
Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with diverse clinical manifestations and symptoms. In the last 10 years, there have been significant advances in understanding the genetic basis for ASD, critically supported through the establishment of ASD bio-collections and application in research. Here, we summarise a selection of major ASD bio-collections and their associated findings. Collectively, these include mapping ASD candidate genes, assessing the nature and frequency of gene mutations and their association with ASD clinical subgroups, insights into related molecular pathways such as the synapses, chromatin remodelling, transcription and ASD-related brain regions. We also briefly review emerging studies on the use of induced pluripotent stem cells (iPSCs) to potentially model ASD in culture. These provide deeper insight into ASD progression during development and could generate human cell models for drug screening. Finally, we provide perspectives concerning the utilities of ASD bio-collections and limitations, and highlight considerations in setting up a new bio-collection for ASD research.
Collapse
Affiliation(s)
- Jamie Reilly
- Regenerative Medicine Institute, School of Medicine, BioMedical Sciences Building, National University of Ireland (NUI), Galway, Ireland
| | - Louise Gallagher
- Trinity Translational Medicine Institute and Department of Psychiatry, Trinity Centre for Health Sciences, St. James Hospital Street, Dublin 8, Ireland
| | - June L. Chen
- Department of Special Education, Faculty of Education, East China Normal University, Shanghai, 200062 China
| | - Geraldine Leader
- Irish Centre for Autism and Neurodevelopmental Research (ICAN), Department of Psychology, National University of Ireland Galway, University Road, Galway, Ireland
| | - Sanbing Shen
- Regenerative Medicine Institute, School of Medicine, BioMedical Sciences Building, National University of Ireland (NUI), Galway, Ireland
| |
Collapse
|
|
27
|
Onore C, Yang H, Van de Water J, Ashwood P. Dynamic Akt/mTOR Signaling in Children with Autism Spectrum Disorder. Front Pediatr 2017; 5:43. [PMID: 28361047 PMCID: PMC5350147 DOI: 10.3389/fped.2017.00043] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 02/15/2017] [Indexed: 12/15/2022] Open
Abstract
Autism spectrum disorder (ASD) is a behaviorally defined disorder affecting 1 in 68 children. Currently, there is no known cause for the majority of ASD cases nor are there physiological diagnostic tools or biomarkers to aid behavioral diagnosis. Whole-genome linkage studies, genome-wide association studies, copy number variation screening, and SNP analyses have identified several ASD candidate genes, but which vary greatly among individuals and family clusters, suggesting that a variety of genetic mutations may result in a common pathology or alter a common mechanistic pathway. The Akt/mammalian target of rapamycin (mTOR) pathway is involved in many cellular processes including synaptic plasticity and immune function that can alter neurodevelopment. In this study, we examined the activity of the Akt/mTOR pathway in cells isolated from children with ASD and typically developing controls. We observed higher activity of mTOR, extracellular receptor kinase, and p70S6 kinase and lower activity of glycogen synthase kinase 3 (GSK3)α and tuberin (TSC2) in cells from children with ASD. These data suggest a phosphorylation pattern indicative of higher activity in the Akt/mTOR pathway in children with general/idiopathic ASD and may suggest a common pathological pathway of interest for ASD.
Collapse
Affiliation(s)
- Charity Onore
- The M.I.N.D. Institute, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| | - Houa Yang
- The M.I.N.D. Institute, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| | - Judy Van de Water
- The M.I.N.D. Institute, University of California Davis, Davis, CA, USA
- Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, USA
| | - Paul Ashwood
- The M.I.N.D. Institute, University of California Davis, Davis, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| |
Collapse
|
|
28
|
Reis VNDS, Kitajima JP, Tahira AC, Feio-dos-Santos AC, Fock RA, Lisboa BCG, Simões SN, Krepischi ACV, Rosenberg C, Lourenço NC, Passos-Bueno MR, Brentani H. Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder. PLoS One 2017; 12:e0170386. [PMID: 28118382 PMCID: PMC5261619 DOI: 10.1371/journal.pone.0170386] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 12/31/2016] [Indexed: 12/30/2022] Open
Abstract
It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations—single nucleotide variants (SNVs) or small insertions and deletions (indels)—with probable functional impacts. With aCGH, we identified, in both siblings, a duplication in the 4p16.3 region and a deletion at 8p23.3, inherited by a paternal balanced translocation, t(4, 8) (p16; p23). Exome variant analysis found a total of 316 variants, of which 102 were shared by both siblings, 128 were in the male sibling exome data, and 86 were in the female exome data. Our integrative network analysis showed that the siblings’ shared translocation could explain their similar syndromic phenotype, including overgrowth, macrocephaly, and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, which are important to the robustness of the network and contribute to the understanding of the broader spectrum of psychiatric symptoms. This study shows the importance of using an integrative approach to explore genotype-phenotype variability.
Collapse
MESH Headings
- Autism Spectrum Disorder/genetics
- Child
- Chromosomes, Human, Pair 4/genetics
- Chromosomes, Human, Pair 4/ultrastructure
- Chromosomes, Human, Pair 8/genetics
- Chromosomes, Human, Pair 8/ultrastructure
- Comparative Genomic Hybridization
- DNA Copy Number Variations
- Exome/genetics
- Female
- Gene Duplication
- Gene Regulatory Networks
- Genetic Association Studies
- Humans
- In Situ Hybridization, Fluorescence
- Intellectual Disability/genetics
- Learning Disabilities/genetics
- Male
- Megalencephaly/genetics
- Nerve Tissue Proteins/genetics
- Nucleic Acid Amplification Techniques
- Sequence Deletion
- Siblings
- Syndrome
- Translocation, Genetic
Collapse
Affiliation(s)
| | | | - Ana Carolina Tahira
- LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Rodrigo Ambrósio Fock
- Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
| | | | - Sérgio Nery Simões
- Department of Informatics, Federal Institute of Espírito Santo, Serra, Brazil
| | - Ana C. V. Krepischi
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil
| | - Carla Rosenberg
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil
| | - Naila Cristina Lourenço
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil
| | - Maria Rita Passos-Bueno
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, São Paulo, Brazil
| | - Helena Brentani
- LIM23-Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil
| |
Collapse
|
|
29
|
Choi H, Song J, Park G, Kim J. Modeling of Autism Using Organoid Technology. Mol Neurobiol 2016; 54:7789-7795. [DOI: 10.1007/s12035-016-0274-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 10/30/2016] [Indexed: 01/01/2023]
|
|
30
|
Ishii K, Kubo KI, Nakajima K. Reelin and Neuropsychiatric Disorders. Front Cell Neurosci 2016; 10:229. [PMID: 27803648 PMCID: PMC5067484 DOI: 10.3389/fncel.2016.00229] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 09/22/2016] [Indexed: 12/22/2022] Open
Abstract
Proper neuronal migration and laminar formation during corticogenesis is essential for normal brain function. Disruption of these developmental processes is thought to be involved in the pathogenesis of some neuropsychiatric conditions. Especially, Reelin, a glycoprotein mainly secreted by the Cajal-Retzius cells and a subpopulation of GABAergic interneurons, has been shown to play a critical role, both during embryonic and postnatal periods. Indeed, animal studies have clearly revealed that Reelin is an essential molecule for proper migration of cortical neurons and finally regulates the cell positioning in the cortex during embryonic and early postnatal stages; by contrast, Reelin signaling is closely involved in synaptic function in adulthood. In humans, genetic studies have shown that the reelin gene (RELN) is associated with a number of psychiatric diseases, including Schizophrenia (SZ), bipolar disorder (BP) and autistic spectrum disorder. Indeed, Reln haploinsufficiency has been shown to cause cognitive impairment in rodents, suggesting the expression level of the Reelin protein is closely related to the higher brain functions. However, the molecular abnormalities in the Reelin pathway involved in the pathogenesis of psychiatric disorders are not yet fully understood. In this article, we review the current progress in the understanding of the Reelin functions that could be related to the pathogenesis of psychiatric disorders. Furthermore, we discuss the basis for selecting Reelin and molecules in its downstream signaling pathway as potential therapeutic targets for psychiatric illnesses.
Collapse
Affiliation(s)
- Kazuhiro Ishii
- Department of Anatomy, Keio University School of Medicine Tokyo, Japan
| | - Ken-Ichiro Kubo
- Department of Anatomy, Keio University School of Medicine Tokyo, Japan
| | - Kazunori Nakajima
- Department of Anatomy, Keio University School of Medicine Tokyo, Japan
| |
Collapse
|
|
31
|
Abstract
Autism is a complex neurodevelopmental disorder, which has captured the attention of not only pediatricians but also the parents. From the symptoms until the final diagnosis, parents undergo a diagnostic odyssey that involves a battery of tests without much yield. This has led to an increase in the referrals to the clinical geneticists to rule out the possible genetic etiology that can have implications for the parents for future pregnancy. This chapter focuses on the various genetic causes and their appropriate application in the evaluation of a child with Autism Spectrum Disorders (ASDs).
Collapse
Affiliation(s)
- Shruthi Sudarshan
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Neerja Gupta
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India.
| | - Madhulika Kabra
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India
| |
Collapse
|
|
32
|
Fraley ER, Burkett ZD, Day NF, Schwartz BA, Phelps PE, White SA. Mice with Dab1 or Vldlr insufficiency exhibit abnormal neonatal vocalization patterns. Sci Rep 2016; 6:25807. [PMID: 27184477 PMCID: PMC4868998 DOI: 10.1038/srep25807] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 04/22/2016] [Indexed: 11/27/2022] Open
Abstract
Genetic and epigenetic changes in components of the Reelin-signaling pathway (RELN, DAB1) are associated with autism spectrum disorder (ASD) risk. Social communication deficits are a key component of the ASD diagnostic criteria, but the underlying neurogenetic mechanisms remain unknown. Reln insufficient mice exhibit ASD-like behavioral phenotypes including altered neonatal vocalization patterns. Reelin affects multiple pathways including through the receptors, Very low-density lipoprotein receptor (Vldlr), Apolipoprotein receptor 2 (Apoer2), and intracellular signaling molecule Disabled-1 (Dab1). As Vldlr was previously implicated in avian vocalization, here we investigate vocalizations of neonatal mice with a reduction or absence of these components of the Reelin-signaling pathway. Mice with low or no Dab1 expression exhibited reduced calling rates, altered call-type usage, and differential vocal development trajectories. Mice lacking Vldlr expression also had altered call repertoires, and this effect was exacerbated by deficiency in Apoer2. Together with previous findings, these observations 1) solidify a role for Reelin in vocal communication of multiple species, 2) point to the canonical Reelin-signaling pathway as critical for development of normal neonatal calling patterns in mice, and 3) suggest that mutants in this pathway could be used as murine models for Reelin-associated vocal deficits in humans.
Collapse
Affiliation(s)
- E R Fraley
- Molecular, Cellular and Integrative Physiology Graduate Program, University of California, Los Angeles, USA.,Department of Integrative Biology and Physiology, University of California, Los Angeles, USA
| | - Z D Burkett
- Molecular, Cellular and Integrative Physiology Graduate Program, University of California, Los Angeles, USA.,Department of Integrative Biology and Physiology, University of California, Los Angeles, USA
| | - N F Day
- Department of Integrative Biology and Physiology, University of California, Los Angeles, USA
| | - B A Schwartz
- Undergraduate Interdepartmental Program in Neuroscience, University of California, Los Angeles, USA
| | - P E Phelps
- Molecular, Cellular and Integrative Physiology Graduate Program, University of California, Los Angeles, USA.,Department of Integrative Biology and Physiology, University of California, Los Angeles, USA
| | - S A White
- Molecular, Cellular and Integrative Physiology Graduate Program, University of California, Los Angeles, USA.,Department of Integrative Biology and Physiology, University of California, Los Angeles, USA
| |
Collapse
|
|
33
|
Katz OL, Krantz ID, Noon SE. Interstitial deletion of 7q22.1q31.1 in a boy with structural brain abnormality, cardiac defect, developmental delay, and dysmorphic features. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2016; 172:92-101. [PMID: 27096924 DOI: 10.1002/ajmg.c.31485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
This report describes a male child with a history of poor feeding and swallowing problems, hypotonia, mild bilateral sensorineural hearing loss, cerebral cortical agenesis, cardiac defects, cyanotic episodes triggered by specific movement, dysmorphic features, and developmental delays. Analysis by CytoScan HD array identified a 12.1 Mb interstitial deletion of 7q22.1q31.1 (98,779,628-110,868,171). We present a comprehensive review of the literature surrounding intermediate 7q deletions that overlap with this child's deletion, and an analysis of candidate genes in the deleted region. © 2016 Wiley Periodicals, Inc.
Collapse
|
|
34
|
Lim D, Strucken EM, Choi BH, Chai HH, Cho YM, Jang GW, Kim TH, Gondro C, Lee SH. Genomic Footprints in Selected and Unselected Beef Cattle Breeds in Korea. PLoS One 2016; 11:e0151324. [PMID: 27023061 PMCID: PMC4811422 DOI: 10.1371/journal.pone.0151324] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 02/26/2016] [Indexed: 01/01/2023] Open
Abstract
Korean Hanwoo cattle have been subjected to intensive artificial selection over the past four decades to improve meat production traits. Another three cattle varieties very closely related to Hanwoo reside in Korea (Jeju Black and Brindle) and in China (Yanbian). These breeds have not been part of a breeding scheme to improve production traits. Here, we compare the selected Hanwoo against these similar but presumed to be unselected populations to identify genomic regions that have been under recent selection pressure due to the breeding program. Rsb statistics were used to contrast the genomes of Hanwoo versus a pooled sample of the three unselected population (UN). We identified 37 significant SNPs (FDR corrected) in the HW/UN comparison and 21 known protein coding genes were within 1 MB to the identified SNPs. These genes were previously reported to affect traits important for meat production (14 genes), reproduction including mammary gland development (3 genes), coat color (2 genes), and genes affecting behavioral traits in a broader sense (2 genes). We subsequently sequenced (Illumina HiSeq 2000 platform) 10 individuals of the brown Hanwoo and the Chinese Yanbian to identify SNPs within the candidate genomic regions. Based on allele frequency differences, haplotype structures, and literature research, we singled out one non-synonymous SNP in the APP gene (APP: c.569C>T, Ala199Val) and predicted the mutational effect on the protein structure. We found that protein-protein interactions might be impaired due to increased exposed hydrophobic surfaces of the mutated protein. The APP gene has also been reported to affect meat tenderness in pigs and obesity in humans. Meat tenderness has been linked to intramuscular fat content, which is one of the main breeding goals for brown Hanwoo, potentially supporting a causal influence of the herein described nsSNP in the APP gene.
Collapse
Affiliation(s)
- Dajeong Lim
- Division of Animal Genomics & Bioinformatics, National Institute of Animal Science, RDA, Jeonju 565–851, Republic of Korea
| | - Eva M. Strucken
- School of Environmental and Rural Science, University of New England, Armidale, NSW Australia
| | - Bong Hwan Choi
- Division of Animal Genomics & Bioinformatics, National Institute of Animal Science, RDA, Jeonju 565–851, Republic of Korea
| | - Han Ha Chai
- Division of Animal Genomics & Bioinformatics, National Institute of Animal Science, RDA, Jeonju 565–851, Republic of Korea
| | - Yong Min Cho
- Division of Animal Genomics & Bioinformatics, National Institute of Animal Science, RDA, Jeonju 565–851, Republic of Korea
| | - Gul Won Jang
- Division of Animal Genomics & Bioinformatics, National Institute of Animal Science, RDA, Jeonju 565–851, Republic of Korea
| | - Tae-Hun Kim
- Division of Animal Genomics & Bioinformatics, National Institute of Animal Science, RDA, Jeonju 565–851, Republic of Korea
| | - Cedric Gondro
- School of Environmental and Rural Science, University of New England, Armidale, NSW Australia
| | - Seung Hwan Lee
- Division of Animal and Dairy Science, Chung Nam National University, Daejeon 305–764, Republic of Korea
- * E-mail:
| |
Collapse
|
|
35
|
In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders. Neural Plast 2015; 2016:9847696. [PMID: 26839720 PMCID: PMC4709762 DOI: 10.1155/2016/9847696] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 09/27/2015] [Indexed: 12/25/2022] Open
Abstract
Rapidly emerging evidence implicates perineuronal nets (PNNs) and extracellular matrix (ECM) molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer's disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the “quadripartite” synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction.
Collapse
|
|
36
|
Yoo H. Genetics of Autism Spectrum Disorder: Current Status and Possible Clinical Applications. Exp Neurobiol 2015; 24:257-72. [PMID: 26713075 PMCID: PMC4688327 DOI: 10.5607/en.2015.24.4.257] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 12/02/2015] [Accepted: 12/02/2015] [Indexed: 12/18/2022] Open
Abstract
Autism spectrum disorder (ASD) is one of the most complex behavioral disorders with a strong genetic influence. The objectives of this article are to review the current status of genetic research in ASD, and to provide information regarding the potential candidate genes, mutations, and genetic loci possibly related to pathogenesis in ASD. Investigations on monogenic causes of ASD, candidate genes among common variants, rare de novo mutations, and copy number variations are reviewed. The current possible clinical applications of the genetic knowledge and their future possibilities are highlighted.
Collapse
Affiliation(s)
- Heejeong Yoo
- Department of Psychiatry, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| |
Collapse
|
|
37
|
Shen Y, Xun G, Guo H, He Y, Ou J, Dong H, Xia K, Zhao J. Association and gene-gene interactions study of reelin signaling pathway related genes with autism in the Han Chinese population. Autism Res 2015; 9:436-42. [PMID: 26285919 DOI: 10.1002/aur.1540] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 07/03/2015] [Accepted: 07/31/2015] [Indexed: 11/08/2022]
Abstract
Autism is a neurodevelopmental disorder with unclear etiology. Reelin had been proposed to participate in the etiology of autism due to its important role in brain development. The goal of this study was to explore the association and gene-gene interactions of reelin signaling pathway related genes (RELN, VLDLR, LRP8, DAB1, FYN, and CDK5) with autism in Han Chinese population. Genotyping data of the six genes were obtained from a recent genome-wide association study performed in 430 autistic children who fulfilled the DSM-IV-TR criteria for autistic disorder, and 1,074 healthy controls. Single marker case-control association analysis and haplotype case-control association analysis were conducted after the data was screened. Multifactor dimensionality reduction (MDR) was applied to further test gene-gene interactions. Neither the single marker nor the haplotype association tests found any significant difference between the autistic group and the control group after permutation test of 1,000 rounds. The 4-locus MDR model (comprising rs6143734, rs1858782, rs634500, and rs1924267 which belong to RELN and DAB1) was determined to be the model with the highest cross-validation consistency (CVC) and testing balanced accuracy. The results indicate that an interaction between RELN and DAB1 may increase the risk of autism in the Han Chinese population. Furthermore, it can also be inferred that the involvement of RELN in the etiology of autism would occur through interaction with DAB1.
Collapse
Affiliation(s)
- Yidong Shen
- Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Guanglei Xun
- Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, China.,Mental Health Center of Shandong Province, Jinan, China
| | - Hui Guo
- Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, China.,State Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Yiqun He
- Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, China.,The Second Affiliated Hospital of Xinxiang Medical College, Xinxiang, China
| | - Jianjun Ou
- Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Huixi Dong
- Institute of Mental Health, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Kun Xia
- State Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Jingping Zhao
- State Key Laboratory of Medical Genetics, Central South University, Changsha, China
| |
Collapse
|
|
38
|
The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 2015; 20:640-6. [PMID: 25092245 DOI: 10.1038/mp.2014.77] [Citation(s) in RCA: 234] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 05/08/2014] [Accepted: 06/17/2014] [Indexed: 12/27/2022]
Abstract
The oxytocin receptor gene (OXTR) has been studied as a risk factor for autism spectrum disorder (ASD) owing to converging evidence from multiple levels of analysis that oxytocin (OXT) has an important role in the regulation of affiliative behavior and social bonding in both nonhuman mammals and humans. Inconsistency in the effect sizes of the OXTR variants included in association studies render it unclear whether OXTR is truly associated with ASD, and, if so, which OXTR single-nucleotide polymorphisms (SNPs) are associated. Thus, a meta-analytic review of extant studies is needed to determine whether OXTR shows association with ASD, and to elucidate which specific SNPs have a significant effect on ASD. The current meta-analysis of 16 OXTR SNPs included 3941 individuals with ASD from 11 independent samples, although analyses of each individual SNP included a subset of this total. We found significant associations between ASD and the SNPs rs7632287, rs237887, rs2268491 and rs2254298. OXTR was also significantly associated with ASD in a gene-based test. The current meta-analysis is the largest and most comprehensive investigation of the association of OXTR with ASD and the findings suggest directions for future studies of the etiology of ASD.
Collapse
|
|
39
|
Ishii K, Nagai T, Hirota Y, Noda M, Nabeshima T, Yamada K, Kubo KI, Nakajima K. Reelin has a preventive effect on phencyclidine-induced cognitive and sensory-motor gating deficits. Neurosci Res 2015; 96:30-6. [PMID: 25573715 DOI: 10.1016/j.neures.2014.12.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 12/26/2014] [Accepted: 12/27/2014] [Indexed: 12/19/2022]
Abstract
Reelin has recently attracted attention because of its connection to several neuropsychiatric diseases. We previously reported the finding that prior transplantation of GABAergic neuron precursor cells into the medial prefrontal cortex (mPFC) of mice significantly prevented the induction of cognitive and sensory-motor gating deficits induced by phencyclidine (PCP). The majority of the precursor cells transplanted into the mPFC of the recipient mice differentiated into members of a somatostatin/Reelin-expressing class of GABAergic interneurons. These findings raised the possibility that Reelin secreted by the transplanted cells plays an important role in preventing the deficits induced by PCP. In this study, we investigated whether Reelin itself has a preventive effect on PCP-induced behavioral phenotypes by injecting conditioned medium containing Reelin into the lateral ventricle of the brains of 6- to 7-week-old male mice before administrating PCP. Behavioral analyses showed that the prior Reelin injection had a preventive effect against induction of the cognitive and sensory-motor gating deficits associated with PCP. Moreover, one of the types of Reelin receptor was found to be expressed by neurons in the mPFC. The results of this study point to the Reelin signaling pathway as a candidate target for the pharmacologic treatment of neuropsychiatric diseases.
Collapse
Affiliation(s)
- Kazuhiro Ishii
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Taku Nagai
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya, Japan
| | - Yuki Hirota
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Mariko Noda
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Toshitaka Nabeshima
- Department of Regional Pharmaceutical Care & Sciences, Meijo University, Nagoya, Japan; NPO Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya, Japan
| | - Ken-ichiro Kubo
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan.
| | - Kazunori Nakajima
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan.
| |
Collapse
|
|
40
|
Chmielewski WX, Beste C. Action control processes in autism spectrum disorder – Insights from a neurobiological and neuroanatomical perspective. Prog Neurobiol 2015; 124:49-83. [DOI: 10.1016/j.pneurobio.2014.11.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 11/03/2014] [Accepted: 11/06/2014] [Indexed: 12/22/2022]
|
|
41
|
Biamonte F, Latini L, Giorgi FS, Zingariello M, Marino R, De Luca R, D'Ilio S, Majorani C, Petrucci F, Violante N, Senofonte O, Molinari M, Keller F. Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice. Neurotoxicology 2014; 45:67-80. [PMID: 25305366 DOI: 10.1016/j.neuro.2014.09.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 09/24/2014] [Accepted: 09/28/2014] [Indexed: 12/30/2022]
Abstract
Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2 ppm in Dams' drinking water), or at a toxic dose (6 ppm Dams' drinking water), based on observations in other rodent species and mice strains. We show that: (a) 2 ppm MeHg does not cause PCs loss in the different animal groups, and does not enhance PCs loss in rl(+/-) males; consistent with a lack of overt neurotoxicity, 2 ppm MeHg per se does not cause behavioral alterations (separation-induced ultrasonic calls in newborns, or sociability and social preference in adults); (b) in stark contrast, 6 ppm MeHg causes a dramatic reduction of PCs number in all groups, irrespective of genotype and sex. Cytochrome C release from mitochondria of PCs is enhanced in 6 ppm MeHg-exposed groups, with a concomitant increase of μ-calpain active subunit. At the behavioral level, 6 ppm MeHg exposure strongly increases ultrasonic vocalizations in all animal groups. Notably, 6 ppm MeHg significantly decreases sociability in rl(+/-) male mice, while the 2 ppm group does not show such as decrease. At a subtoxic dose, MeHg does not enhance the autism-like phenotype of male rl(+/-) mice. At the higher MeHg dose, the scenario is more complex, with some "autism-like" features (loss of sociability, preference for sameness) being evidently affected only in rl(+/-) males, while other neuropathological and behavioral parameters being altered in all groups, independently from genotype and sex. Mitochondrial abnormalities appear to play a crucial role in the observed effects.
Collapse
Affiliation(s)
- Filippo Biamonte
- Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy
| | - Laura Latini
- Santa Lucia Foundation, I.R.C.C.S., Via del Fosso di Fiorano 64, 00143 Rome, Italy
| | - Filippo Sean Giorgi
- Section of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy
| | | | - Ramona Marino
- Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy
| | - Roberto De Luca
- Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy
| | - Sonia D'Ilio
- Istituto Superiore di Sanità, Centro Nazionale Sostanze Chimiche, Viale Regina Elena 299, Rome, Italy
| | - Costanza Majorani
- Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy
| | - Francesco Petrucci
- Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy
| | - Nicola Violante
- Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy
| | - Oreste Senofonte
- Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy
| | - Marco Molinari
- Santa Lucia Foundation, I.R.C.C.S., Via del Fosso di Fiorano 64, 00143 Rome, Italy.
| | - Flavio Keller
- Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy.
| |
Collapse
|
|
42
|
Berbel P, Navarro D, Román GC. An evo-devo approach to thyroid hormones in cerebral and cerebellar cortical development: etiological implications for autism. Front Endocrinol (Lausanne) 2014; 5:146. [PMID: 25250016 PMCID: PMC4158880 DOI: 10.3389/fendo.2014.00146] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 08/25/2014] [Indexed: 12/11/2022] Open
Abstract
The morphological alterations of cortical lamination observed in mouse models of developmental hypothyroidism prompted the recognition that these experimental changes resembled the brain lesions of children with autism; this led to recent studies showing that maternal thyroid hormone deficiency increases fourfold the risk of autism spectrum disorders (ASD), offering for the first time the possibility of prevention of some forms of ASD. For ethical reasons, the role of thyroid hormones on brain development is currently studied using animal models, usually mice and rats. Although mammals have in common many basic developmental principles regulating brain development, as well as fundamental basic mechanisms that are controlled by similar metabolic pathway activated genes, there are also important differences. For instance, the rodent cerebral cortex is basically a primary cortex, whereas the primary sensory areas in humans account for a very small surface in the cerebral cortex when compared to the associative and frontal areas that are more extensive. Associative and frontal areas in humans are involved in many neurological disorders, including ASD, attention deficit-hyperactive disorder, and dyslexia, among others. Therefore, an evo-devo approach to neocortical evolution among species is fundamental to understand not only the role of thyroid hormones and environmental thyroid disruptors on evolution, development, and organization of the cerebral cortex in mammals but also their role in neurological diseases associated to thyroid dysfunction.
Collapse
Affiliation(s)
- Pere Berbel
- Departamento de Histología y Anatomía, Facultad de Medicina, Universidad Miguel Hernández, Alicante, Spain
| | - Daniela Navarro
- Departamento de Histología y Anatomía, Facultad de Medicina, Universidad Miguel Hernández, Alicante, Spain
| | - Gustavo C. Román
- Department of Neurology, Weill Cornell Medical College, Cornell University, New York, NY, USA
- Methodist Neurological Institute, Houston, TX, USA
| |
Collapse
|
|
43
|
Genomic and genetic aspects of autism spectrum disorder. Biochem Biophys Res Commun 2014; 452:244-53. [PMID: 25173933 DOI: 10.1016/j.bbrc.2014.08.108] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 08/21/2014] [Indexed: 01/22/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. The past decade has witnessed tremendous progress in the genetic studies of ASD. In this article, we review the accumulating literatures on the monogenic forms of ASD and chromosomal abnormalities associated with ASD, the genome-wide linkage and association studies, the copy number variation (CNV) and the next generation sequencing (NGS) studies. With more than hundreds of mutations being implicated, the convergent biological pathways are emerging and the genetic landscape of ASD becomes clearer. The genetic studies provide a solid basis for future translational study for better diagnoses, intervention and treatment of ASD.
Collapse
|
|
44
|
Michetti C, Romano E, Altabella L, Caruso A, Castelluccio P, Bedse G, Gaetani S, Canese R, Laviola G, Scattoni ML. Mapping pathological phenotypes in reelin mutant mice. Front Pediatr 2014; 2:95. [PMID: 25237666 PMCID: PMC4154529 DOI: 10.3389/fped.2014.00095] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 08/21/2014] [Indexed: 11/20/2022] Open
Abstract
Autism Spectrum Disorders (ASD) are neurodevelopmental disorders with multifactorial origin characterized by social communication deficits and the presence of repetitive behaviors/interests. Several studies showed an association between the reelin gene mutation and increased risk of ASD and a reduced reelin expression in some brain regions of ASD subjects, suggesting a role for reelin deficiency in ASD etiology. Reelin is a large extracellular matrix glycoprotein playing important roles during development of the central nervous system. To deeply investigate the role of reelin dysfunction as vulnerability factor in ASD, we assessed the behavioral, neurochemical, and brain morphological features of reeler male mice. We recently reported a genotype-dependent deviation in the ultrasonic vocal repertoire and a general delay in motor development of reeler pups. We now report that adult male heterozygous (Het) reeler mice did not show social behavior and communication deficits during male-female social interactions. Wildtype and Het mice showed a typical light/dark locomotor activity profile, with a peak during the central interval of the dark phase. However, when faced with a mild stressful stimulus (a saline injection) only Het mice showed an over response to stress. In addition to the behavioral studies, we conducted high performance liquid chromatography and magnetic resonance imaging and spectroscopy to investigate whether reelin mutation influences brain monoamine and metabolites levels in regions involved in ASD. Low levels of dopamine in cortex and high levels of glutamate and taurine in hippocampus were detected in Het mice, in line with clinical data collected on ASD children. Altogether, our data detected subtle but relevant neurochemical abnormalities in reeler mice supporting this mutant line, particularly male subjects, as a valid experimental model to estimate the contribution played by reelin deficiency in the global ASD neurobehavioral phenotype.
Collapse
Affiliation(s)
- Caterina Michetti
- Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy ; Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome , Rome , Italy
| | - Emilia Romano
- Behavioural Neuroscience Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy ; Bambino Gesù Children's Hospital, Istituto Di Ricovero e Cura a Carattere Scientifico , Rome , Italy
| | - Luisa Altabella
- Molecular and Cellular Imaging Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy
| | - Angela Caruso
- Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy ; Department of Psychology, School of Behavioural Neuroscience, Sapienza University of Rome , Rome , Italy
| | - Paolo Castelluccio
- Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy
| | - Gaurav Bedse
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome , Rome , Italy
| | - Silvana Gaetani
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome , Rome , Italy
| | - Rossella Canese
- Molecular and Cellular Imaging Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy
| | - Giovanni Laviola
- Behavioural Neuroscience Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy
| | - Maria Luisa Scattoni
- Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome , Italy
| |
Collapse
|
|
45
|
Pitkänen A, Ndode-Ekane XE, Łukasiuk K, Wilczynski GM, Dityatev A, Walker MC, Chabrol E, Dedeurwaerdere S, Vazquez N, Powell EM. Neural ECM and epilepsy. PROGRESS IN BRAIN RESEARCH 2014; 214:229-62. [DOI: 10.1016/b978-0-444-63486-3.00011-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
46
|
Iodine Deficiency in Egyptian Autistic Children and Their Mothers: Relation to Disease Severity. Arch Med Res 2013; 44:555-61. [DOI: 10.1016/j.arcmed.2013.09.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 09/23/2013] [Indexed: 11/19/2022]
|
|
47
|
Fu X, Mei Z, Sun L. Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population. Genet Mol Biol 2013; 36:486-9. [PMID: 24385848 PMCID: PMC3873176 DOI: 10.1590/s1415-47572013005000037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 06/20/2013] [Indexed: 11/25/2022] Open
Abstract
Autism is a childhood neuro-developmental disorder, and Reelin (RELN) is an important candidate gene for influencing autism. This study aimed at investigating the influence of genetic variants of the RELN gene on autism susceptibility. In this study, 205 autism patients and 210 healthy controls were recruited and the genetic variants of the RELN gene were genotyped by the created restriction site-polymerase chain reaction (CRS-PCR) method. The influence of genetic variants on autism susceptibility was analyzed by association analysis, and the g.296596G > A genetic variant in exon10 of the RELN gene was detected. The frequencies of allele/genotype in autistic patients were significantly different from those in healthy controls, and a statistically significant association was detected between this genetic variant and autism susceptibility. Our data lead to the inference that the g.296596G > A genetic variant in the RELN gene has a potential influence on autism susceptibility in the Chinese Han population.
Collapse
Affiliation(s)
- Xiaoyan Fu
- Department of Pediatrics, Tongji Hospital of Tongji University, Shanghai, People's Republic of China
| | - Zhu Mei
- Department of Pediatrics, Tongji Hospital of Tongji University, Shanghai, People's Republic of China
| | - Lixin Sun
- Department of Pediatrics, Tongji Hospital of Tongji University, Shanghai, People's Republic of China
| |
Collapse
|
|
48
|
Ha S, Stottmann RW, Furley AJ, Beier DR. A forward genetic screen in mice identifies mutants with abnormal cortical patterning. ACTA ACUST UNITED AC 2013; 25:167-79. [PMID: 23968836 DOI: 10.1093/cercor/bht209] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain.
Collapse
Affiliation(s)
- Seungshin Ha
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA 98101, USA
| | - Rolf W Stottmann
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Divisions of Human Genetics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA and
| | - Andrew J Furley
- Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, UK
| | - David R Beier
- Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA 98101, USA
| |
Collapse
|
|
49
|
Won H, Mah W, Kim E. Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci 2013; 6:19. [PMID: 23935565 PMCID: PMC3733014 DOI: 10.3389/fnmol.2013.00019] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 07/16/2013] [Indexed: 12/24/2022] Open
Abstract
Autism spectrum disorder (ASD) is a group of developmental disabilities characterized by impairments in social interaction and communication and restricted and repetitive interests/behaviors. Advances in human genomics have identified a large number of genetic variations associated with ASD. These associations are being rapidly verified by a growing number of studies using a variety of approaches, including mouse genetics. These studies have also identified key mechanisms underlying the pathogenesis of ASD, many of which involve synaptic dysfunctions, and have investigated novel, mechanism-based therapeutic strategies. This review will try to integrate these three key aspects of ASD research: human genetics, animal models, and potential treatments. Continued efforts in this direction should ultimately reveal core mechanisms that account for a larger fraction of ASD cases and identify neural mechanisms associated with specific ASD symptoms, providing important clues to efficient ASD treatment.
Collapse
Affiliation(s)
- Hyejung Won
- Department of Biological Sciences, Korea Advanced Institute of Science and TechnologyDaejeon, South Korea
| | - Won Mah
- Department of Biological Sciences, Korea Advanced Institute of Science and TechnologyDaejeon, South Korea
- Center for Synaptic Brain Dysfunctions, Institute for Basic ScienceDaejeon, South Korea
| | - Eunjoon Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and TechnologyDaejeon, South Korea
- Center for Synaptic Brain Dysfunctions, Institute for Basic ScienceDaejeon, South Korea
| |
Collapse
|
|
50
|
Li J, Liu J, Zhao L, Ma Y, Jia M, Lu T, Ruan Y, Li Q, Yue W, Zhang D, Wang L. Association study between genes in Reelin signaling pathway and autism identifies DAB1 as a susceptibility gene in a Chinese Han population. Prog Neuropsychopharmacol Biol Psychiatry 2013; 44:226-32. [PMID: 23333377 DOI: 10.1016/j.pnpbp.2013.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 12/26/2012] [Accepted: 01/05/2013] [Indexed: 01/07/2023]
Abstract
Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. The genetic factors might play an important role in its pathogenesis. Previous studies revealed that Reelin (RELN) polymorphisms were associated with autism. However, the roles of genes in Reelin signaling pathway for autism are largely unknown. As several knockout mice models in which the Reelin pathway genes (i.e. DAB1, VLDLR/APOER2, FYN/SRC and CRK/CRKL) are deficient have the similar phenotype as the reeler mice (Reelin(-/-)), we hypothesized that the Reelin signaling pathway genes might play roles in the etiology of autism. Therefore, we conducted a family-based association study. Sixty-two tagged single nucleotide polymorphisms (SNPs) covering 15 genes in Reelin pathway were genotyped in 239 trios, and 14 significant SNPs were further investigated in the additional 188 trios. In the total 427 trios, we found significant genetic association between autism and four SNPs in DAB1 (rs12035887 G: p=0.0006; rs3738556 G: p=0.0044; rs1202773 A: p=0.0048; rs12740765 T: p=0.0196). After the Bonferroni correction, SNP rs12035887 remained significant. Furthermore, the haplotype constructed with rs1202773 and rs12023109 in DAB1 showed significant excess transmission in both individual and global haplotype analyses (p=0.0052 and 0.0279, respectively). Our findings suggested that variations in DAB1 involved in the Reelin signaling pathway might contribute to genetic susceptibility to autism with Chinese Han decent, supporting the defect in the Reelin signaling pathway as a predisposition factor for autism.
Collapse
Affiliation(s)
- Jun Li
- Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, PR China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|