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 eIF2a 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 eIF2a 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 eIF2a effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2a pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2a signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.
Friday, November 2, 2018
Nicole Calakos, MD, PhD, Associate Professor of Neurology and Neurobiology, Duke University Medical School, presents the Neurology/Neuroscience Research Seminar on Friday, November 2nd
ROOM 5515 BIOMEDICAL SCIENCE RESEARCH BUILDING (BSRB), 109 ZINA PITCHER PLACE, ANN ARBOR, MI 48109
“Found in Translation: A Pathway Mechanism for Dystonias Involving eIF2alpha-dependent Regulation of Protein Synthesis”