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.
The proposed high-throughput screening assay has the potential to identify new drug targets for the treatment of dystonia, a disabling motor disorder that persists throughout adulthood. DYT1 dystonia is specifically targeted in this assay. DYT1 dystonia is the most common inherited form of primary dystonia. DYt1 dystonia commonly begins in childhood and is unremitting.
|Rittiner, Joseph E; Caffall, Zachary F; Hernández-Martinez, Ricardo et al. (2016) Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2? Signaling as a Generalizable Mechanism for Dystonia. Neuron 92:1238-1251|