DYT1 dystonia is a neurodevelopmental disease caused by a deletion (?gag;?E) in the Tor1a gene encoding torsinA. Although this mutation was discovered in 1997, it is unknown whether the ?E mutation causes abnormal movements though a gain or loss of function mechanism. Confounding this issue, it is unclear when the ?E mutation disrupts development and function of the motor system. These questions are conceptually and practically important because their answers are urgently needed to advance understanding of dystonia pathogenesis and to begin to design rationally targeted therapies (e.g., knowing that torsinA loss of function causes abnormal movement would suggest a search for torsinA-activating compounds). A major barrier to unraveling the mechanism of the ?E mutation that causes dystonia is the absence of a torsinA-based mouse model that develops overt abnormal movements. In this application, we describe the development of the first such model with overt dystonic-like twisting movements. Moreover, we have developed a related set of torsinA-based mouse models that will enable us to delete torsinA or induce the endogenous expression of ?E-torsinA in the developing or mature CNS. Our extensive preliminary data based on these models has already enabled us to make a series of exciting observations linking the ?E mutation, torsinA loss- of-function, motor circuit-selective molecular pathology and abnormal twisting movements. These data also identify the torsinA homolog torsinB as a powerful modulator of torsinA phenotypes, providing mechanistic insight into dystonia pathogenesis. We propose to use these novel models 1) to define the mechanism of the ?E mutation that causes abnormal movements;2) to determine when during neural development the critical events occur and;3) to test the hypothesis that torsinB is a critical determinant of CNS sensitivity to torsinA dysfunction that can be used to suppress or prevent DYT1 dystonia.

Public Health Relevance

DYT1 dystonia is an incurable brain disease of childhood caused by a mutation in the gene encoding the torsinA protein. The effect of this mutation on torsinA function is unknown. This proposal employs novel mouse models of DYT1 dystonia to determine the effect of the DYT1 mutation on torsinA function, and tests a novel approach to prevent or suppress the symptoms of the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Sieber, Beth-Anne
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University of Michigan Ann Arbor
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Pappas, Samuel S; Liang, Chun-Chi; Kim, Sumin et al. (2018) TorsinA dysfunction causes persistent neuronal nuclear pore defects. Hum Mol Genet 27:407-420
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Pappas, Samuel S; Darr, Katherine; Holley, Sandra M et al. (2015) Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons. Elife 4:e08352

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