title: Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.
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.
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rittiner
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Zachary F
authors.initials: ZF
authors.lastname: Caffall
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Hernández-Martinez
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Sydney M
authors.initials: SM
authors.lastname: Sanderson
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27708, USA; Department of RNAi Screening Facility, Duke University, Durham, NC 27708, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Pearson
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Kaylin K
authors.initials: KK
authors.lastname: Tsukayama
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Liu
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Changrui
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Tracy
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Miranda K
authors.initials: MK
authors.lastname: Shipman
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hickey
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Burton
authors.initials: B
authors.lastname: Scott
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27708, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Stacy
authors.affiliation: 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.
authors.forename: Rachel
authors.initials: R
authors.lastname: Saunders-Pullman
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Bressman
authors.affiliation: 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.
authors.forename: Kristina
authors.initials: K
authors.lastname: Simonyan
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nutan
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.affiliation: 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.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Cirulli
authors.affiliation: 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.
authors.forename: Nicole
authors.initials: N
authors.lastname: Calakos
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics* / Q000378:metabolism; D004422:Dystonia Musculorum Deformans / Q000235:genetics; D020821:Dystonic Disorders / Q000235:genetics* / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D023281:Genomics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics; D009473:Neuronal Plasticity; D015398:Signal Transduction; D014103:Torticollis / Q000235:genetics
chemical_list: C497109:ATF4 protein, human; D015852:Eukaryotic Initiation Factor-2; D018832:Molecular Chaperones; C108175:TOR1A protein, human; D051701:Activating Transcription Factor 4
keywords: dystonia; regulation of translation; stress signaling