Neuron
Volume 92, Issue 6, 21 December 2016, Pages 1238-1251
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Article
Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia

https://doi.org/10.1016/j.neuron.2016.11.012Get rights and content
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Highlights

  • Genome-wide RNAi screen of a novel DYT1 dystonia assay identifies the eIF2α pathway

  • Enhancing eIF2α signaling restores absent corticostriatal LTD in DYT1 knockin mice

  • DYT1 dystonia patient-derived cells have a deficient eIF2α pathway stress response

  • Rare loss-of-function variants in ATF4 are enriched in sporadic dystonia patients

Summary

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. 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.

Keywords

dystonia
stress signaling
regulation of translation

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