Publication Date:
2014-08-19
Description:
Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the biological basis of schizophrenia. Although this hypothesis has gained indirect support from human post-mortem brain analyses and genetic studies, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501856/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501856/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Zhexing -- Nguyen, Ha Nam -- Guo, Ziyuan -- Lalli, Matthew A -- Wang, Xinyuan -- Su, Yijing -- Kim, Nam-Shik -- Yoon, Ki-Jun -- Shin, Jaehoon -- Zhang, Ce -- Makri, Georgia -- Nauen, David -- Yu, Huimei -- Guzman, Elmer -- Chiang, Cheng-Hsuan -- Yoritomo, Nadine -- Kaibuchi, Kozo -- Zou, Jizhong -- Christian, Kimberly M -- Cheng, Linzhao -- Ross, Christopher A -- Margolis, Russell L -- Chen, Gong -- Kosik, Kenneth S -- Song, Hongjun -- Ming, Guo-li -- AG045656/AG/NIA NIH HHS/ -- F31 MH102978/MH/NIMH NIH HHS/ -- MH087874/MH/NIMH NIH HHS/ -- MH102978/MH/NIMH NIH HHS/ -- NS047344/NS/NINDS NIH HHS/ -- NS048271/NS/NINDS NIH HHS/ -- R01 AG024984/AG/NIA NIH HHS/ -- R01 AG045656/AG/NIA NIH HHS/ -- R01 MH083911/MH/NIMH NIH HHS/ -- R01 MH105128/MH/NIMH NIH HHS/ -- R01 NS047344/NS/NINDS NIH HHS/ -- R01 NS048271/NS/NINDS NIH HHS/ -- R21 ES021957/ES/NIEHS NIH HHS/ -- R21 MH092740/MH/NIMH NIH HHS/ -- T32 GM008752/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):414-8. doi: 10.1038/nature13716. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3]. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3]. ; 1] Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA [2]. ; Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology, Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Japan. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [4] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132547" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Differentiation
;
Fibroblasts
;
Glutamine/metabolism
;
Humans
;
Induced Pluripotent Stem Cells/metabolism/*pathology
;
Male
;
Mental Disorders/genetics/metabolism/*pathology
;
Mice
;
Mutant Proteins/genetics/metabolism
;
Mutation/genetics
;
Nerve Tissue Proteins/genetics/metabolism
;
Neurons/cytology/metabolism/pathology
;
Pedigree
;
Presynaptic Terminals/metabolism/pathology
;
Prosencephalon/metabolism/pathology
;
Protein Binding
;
Synapses/metabolism/*pathology
;
Transcriptome
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
