Novel Genetic Mouse Model to Study the Consequences of TorsinA Dysfunction

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DESCRIPTION (provided by applicant): Dystonia is among the top 3 prevalent movement disorders and a cause of unremitting disability from a relatively young onset. As yet, its mechanisms are largely unknown. It is not considered a neurodegenerative disease and abnormalities in brain plasticity are suggested. In a patient with sporadic, late-onset, focal dystonia, we recently identified a novel rare sequence variant of TOR1A (p.F205I). TOR1A mutation is a known cause of familial early-onset, generalized dystonia (DYT1, c.GAG). After revealing in silico and in vitro evidence that the p.F205I variant impairs TorsinA function, we developed a knockin mutation mouse model to test the behavioral significance. In preliminary studies, we have found that F205I mutant mice have robust and replicable behavioral abnormalities in a motor learning task. We propose to further develop this novel mouse model and use it to understand the changes in brain activity and neuropathology due to F205I TorsinA and their relationship to behavior. The F205I TOR1A mouse model provides a useful tool to establish the causal relationship between TorsinA dysfunction, neuronal pathology and altered behavior. By furthering knowledge of TorsinA biology, we hope to accelerate insights for the treatment of dystonia.