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

Autor:	Rittiner JE; Department of Neurology, Duke University, Durham, NC 27708, USA., Caffall ZF; Department of Neurology, Duke University, Durham, NC 27708, USA., Hernández-Martinez R; Department of Neurology, Duke University, Durham, NC 27708, USA., Sanderson SM; Department of Neurology, Duke University, Durham, NC 27708, USA., Pearson JL; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27708, USA; Department of RNAi Screening Facility, Duke University, Durham, NC 27708, USA., Tsukayama KK; Department of Neurology, Duke University, Durham, NC 27708, USA., Liu AY; Department of Neurology, Duke University, Durham, NC 27708, USA., Xiao C; Department of Neurology, Duke University, Durham, NC 27708, USA., Tracy S; Department of Neurology, Duke University, Durham, NC 27708, USA., Shipman MK; Department of Neurology, Duke University, Durham, NC 27708, USA., Hickey P; Department of Neurology, Duke University, Durham, NC 27708, USA., Johnson J; Department of Neurology, Duke University, Durham, NC 27708, USA., Scott B; Department of Neurology, Duke University, Durham, NC 27708, USA., Stacy M; Department of Neurology, Duke University, Durham, NC 27708, USA., Saunders-Pullman R; Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, NY 10003, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Bressman S; Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, NY 10003, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Simonyan K; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Sharma N; Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA., Ozelius LJ; Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA., Cirulli ET; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27708, USA; Center for Applied Genomics and Precision Medicine, Duke University, Durham, NC 27708, USA., Calakos N; Department of Neurology, Duke University, Durham, NC 27708, USA; Department of Neurobiology, Duke University, Durham, NC 27708, USA. Electronic address: nicole.calakos@dm.duke.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2016 Dec 21; Vol. 92 (6), pp. 1238-1251. Date of Electronic Publication: 2016 Dec 08.
DOI:	10.1016/j.neuron.2016.11.012
Abstrakt:	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. (Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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