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.
Dystonia is an involuntary movement disorder that is a cause of significant disability. The pathogenesis of dystonia remains unclear. Consequently, current treatment modalities have both limited efficacy and significant side effects. We propose to develop a novel animal model based on a rare TOR1A sequence variant identified in an individual with late-onset, focal dystonia. This novel mouse model has the potential to provide critical insights into the relationship between TorsinA dysfunction and behavioral sequelae. These studies will advance our understanding of the contribution of this gene to dystonia and related neurological diseases.