Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.
Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.
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DOI：
10.1016/j.neuron.2016.11.012
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发表时间：
2016-12-21
期刊：
影响因子：
16.2
通讯作者：
Calakos N
中科院分区：
文献类型：
--
作者：
Rittiner JE;Caffall ZF;Hernández-Martinez R;Sanderson SM;Pearson JL;Tsukayama KK;Liu AY;Xiao C;Tracy S;Shipman MK;Hickey P;Johnson J;Scott B;Stacy M;Saunders-Pullman R;Bressman S;Simonyan K;Sharma N;Ozelius LJ;Cirulli ET;Calakos N
肌张力障碍是一种大脑疾病，导致不自主的，往往是痛苦的运动。除了某些形式的多巴胺缺乏的作用外，大多数肌张力障碍的细胞机制目前尚不清楚。在这里，我们通过全基因组RNAi筛选发现了eIF 2 α信号缺陷在DYT 1肌张力障碍中的作用，DYT 1肌张力障碍是一种罕见的遗传性全身性形式。随后的实验包括患者源性细胞和小鼠模型，支持eIF 2 α通路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颈肌张力障碍患者存在类似的通路损伤，这是由于eIF 2 α效应子ATF 4/CREB 2的罕见编码变异所致。还考虑到另一种肌张力障碍DYT 16涉及eIF 2 α通路上游的基因，这些结果在机制上将多种形式的肌张力障碍联系起来，并提出了肌张力障碍发病机制的新的整体细胞机制-eIF 2 α信号传导受损，这是一种已知在细胞应激反应和突触可塑性中发挥作用的通路。
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 eIF2α 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 eIF2α 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 eIF2α effector ATF4/CREB2. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2α pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis – impairment of eIF2α signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.