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首页> 外文期刊>Neuron >Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2 alpha Signaling as a Generalizable Mechanism for Dystonia
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Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2 alpha Signaling as a Generalizable Mechanism for Dystonia

机译：孟德尔和零星疾病的功能基因组分析确定受损的eIF2 alpha信号传导是肌张力障碍的普遍机制

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摘要

Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2 alpha signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2 alpha pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2 alpha effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2 alpha pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2 alpha signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.
机译：肌张力障碍是一种脑部疾病，引起不自主的，通常是痛苦的运动。除了某些形式的多巴胺缺乏症的作用外，目前大多数肌张力障碍的细胞机制尚不清楚。在这里，我们通过全基因组RNAi筛选发现DYT1肌张力障碍中罕见eIF2 alpha信号传导的作用，这是一种罕见的遗传普遍形式。随后的实验（包括患者来源的细胞和小鼠模型）支持eIF2α途径扰动的致病作用和治疗潜力。我们进一步发现遗传和功能证据支持散发性宫颈肌张力障碍患者的类似途径损伤，这是由于eIF2α效应子ATF4的罕见编码变异所致。还考虑到另一种肌张力障碍DYT16涉及eIF2 alpha途径的上游基因，这些结果将肌张力障碍的多种形式机械地联系起来，并提出了一种新的总体细胞机制，用于肌张力障碍的发病机理，eIF2α信号传导的损伤（该途径以其作用而闻名）在细胞应激反应和突触可塑性。

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