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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • December 21, 2016

Published In

Volume / Issue

  • 92 / 6

Start / End Page

  • 1238 - 1251

PubMed ID

  • 27939583

Pubmed Central ID

  • 27939583

Electronic International Standard Serial Number (EISSN)

  • 1097-4199

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2016.11.012

Language

  • eng

Conference Location

  • United States