Novel high-throughput screening for modifiers of TorsinA pathology

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): The TOR1A gene encodingTorsinA protein is mutated in the most common form of inherited primary dystonia, DYT1. Both our understanding of the cellular biology and efficacy of treatments is very limited for dystonia. The human DYT1 disease-causing mutation, deltaGAG causes major cellular disruption of membrane flow and fluorescent indicators of TorsinA show an irregular punctuate pattern (inclusions). We hypothesize that the identification of modifiers of cellular inclusion pathology caused by mutant TorsinA proteins will provide novel targets to advance both our understanding of dystonia pathogenesis and to provide novel targets for the treatment of dystonia. Using a novel high-throughput assay that our group recently developed, we propose to perform whole genome RNAi screening for modifiers that normalize mutant TorsinA-associated cellular pathology. We expect that this screen because of its comprehensive scope and unbiased nature may identify novel therapeutic candidates and further suggest entire signaling pathways to target for the treatment of dystonia.