Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia

Joseph E. Rittiner, Zachary F. Caffall, Ricardo Hernández-Martinez, Sydney M. Sanderson, James L. Pearson, Kaylin K. Tsukayama, Anna Y. Liu, Changrui Xiao, Samantha Tracy, Miranda K. Shipman, Patrick Hickey, Julia Johnson, Burton Scott, Mark Stacy, Rachel Saunders-Pullman, Susan Bressman, Kristina Simonyan, Nutan Sharma, Laurie J. Ozelius, Elizabeth T. CirulliNicole Calakos

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1238-1251
Number of pages14
JournalNeuron
Volume92
Issue number6
DOIs
StatePublished - 21 Dec 2016

Keywords

  • dystonia
  • regulation of translation
  • stress signaling

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