Synaptic dysregulation in a human iPS cell model of mental disorders
| Autor: | Elmer Guzman, Georgia Makri, Guo Li Ming, Namshik Kim, Gong Chen, Jizhong Zou, David W. Nauen, Xinyuan Wang, Cheng Hsuan Chiang, Russell L. Margolis, Matthew A. Lalli, Ziyuan Guo, Christopher A. Ross, Linzhao Cheng, Ce Zhang, Hongjun Song, Jaehoon Shin, Kimberly M. Christian, Huimei Yu, Yijing Su, Nadine Yoritomo, Ki Jun Yoon, Kenneth S. Kosik, Zhexing Wen, Kozo Kaibuchi, Ha Nam Nguyen |
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| Rok vydání: | 2014 |
| Předmět: |
Male
General Science & Technology Glutamine Induced Pluripotent Stem Cells Presynaptic Terminals Nerve Tissue Proteins Biology medicine.disease_cause Article Frameshift mutation Synapse DISC1 Mice Prosencephalon medicine Animals Humans Induced pluripotent stem cell Genetics Neurons Mutation Multidisciplinary Mental Disorders Cell Differentiation Fibroblasts medicine.disease Penetrance Pedigree Schizophrenia Forebrain Synapses biology.protein Mutant Proteins Transcriptome Protein Binding |
| Zdroj: | Nature, vol 515, iss 7527 Wen, Z; Nguyen, HN; Guo, Z; Lalli, MA; Wang, X; Su, Y; et al.(2014). Synaptic dysregulation in a human iPS cell model of mental disorders. Nature, 515(7527), 414-418. doi: 10.1038/nature13716. UC Santa Barbara: Retrieved from: http://www.escholarship.org/uc/item/1xx2j04b |
| Popis: | Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders1, and ‘a disease of synapses’ is the major hypothesis for the biological basis of schizophrenia2. Although this hypothesis has gained indirect support from human post-mortem brain analyses2–4 and genetic studies5–10, 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 phenotypes11. 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 disorders12 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. |
| Databáze: | OpenAIRE |
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