Synaptic dysregulation in a human iPS cell model of mental disorders.
Synaptic dysregulation in a human iPS cell model of mental disorders.
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DOI：
10.1038/nature13716
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发表时间：
2014-11-20
期刊：
影响因子：
64.8
通讯作者：
Ming GL
中科院分区：
文献类型：
--
作者：
Wen Z;Nguyen HN;Guo Z;Lalli MA;Wang X;Su Y;Kim NS;Yoon KJ;Shin J;Zhang C;Makri G;Nauen D;Yu H;Guzman E;Chiang CH;Yoritomo N;Kaibuchi K;Zou J;Christian KM;Cheng L;Ross CA;Margolis RL;Chen G;Kosik KS;Song H;Ming GL
神经发育失调与结构和功能连接的改变被认为是许多神经精神疾病的基础，“突触疾病”是精神分裂症生物学基础的主要假设。虽然这一假设已经从人类死后大脑分析和遗传研究中获得了间接支持，但人们对患者神经元突触的病理生理学以及精神障碍的易感基因如何导致人类突触缺陷知之甚少。大多数精神疾病的遗传学是非常复杂的，由于多种易感性变体具有低遗传率和可变的表型。罕见的，多重影响，大家庭，其中一个单一的遗传位点可能是负责赋予易感性已被证明是非常宝贵的复杂疾病的研究。在这里，我们从一个家族的四个成员中产生了诱导多能干细胞（iPS），其中精神分裂症1（DISC1）中的移码突变与主要精神疾病共分离，我们通过基因编辑进一步产生了不同的同基因iPS细胞系。我们发现，突变DISC1导致突触囊泡释放缺陷的iPS细胞衍生的前脑神经元。突变DISC1耗尽野生型DISC1蛋白，并且，此外，在人前脑神经元中与突触和精神疾病相关的许多基因的表达失调。我们的研究揭示了精神疾病相关突变导致人类神经元突触缺陷和转录失调，我们的发现为精神疾病的分子和突触病因学提供了新的见解。
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.