The long term goals of this project are to understand the role of torsinA in brain development and establish a link between torsinA function and the pathogenesis of early onset torsion dystonia. TorsinA is the product of the DYT1 gene. Mutations in DYT1 are linked to early onset torsion dystonia (DYTl dystonia), the most common form of torsion dystonia. Torsins are members of the AAA+ superfamily of proteins that typically mediate conformational changes in protein complexes. The majority of TorsinA is localized withih the endoplasmic reticulum and the contiguous nuclear envelope where it links the nuclear envelope with the cytoskeleton. In this location, torsinA is implicated in organelle movement, including nuclear translocation in dividing and migrating cells. The experiments proposed here wiil test the hypothesis that torsinA plays critical roles in neurogenesis and neuronal migration in the developing brain. Understanding the role of torsinA in CNS development is essential for correlating the biological functions of torsins with pathogenesis of early onset torsion dystonia. The disease process is not linked yet to specific cell and molecular mechanisms. Therefore, constructing mechanistic models of the disease requires information on the role of torsinA in the CNS. Since the symptoms of early onset torsion dystonia implicate basal ganglia dysfunction as well as GABAergic and dopaminergic imbalances, the proposed experiments will focus on the development of the GABA and dopamine systems in the basal ganglia. The experiments will use DYT1 knockout mice as well as DYTl delGAG knock-in mice as loss or gain of function models to study the role of torsinA in neurogenesis and neuronal migration. The data are expected to provide insights into the role of torsinA in brain development, at the cellular and systems level. The data when taken together with the data from the other projects in the program will be significant for linking the biological function of torsinA with the pathogenesis of early onset torsion dystonia and for developing mechanistic models and treatment paradigms for the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Special Emphasis Panel (ZNS1-SRB-B)
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Massachusetts General Hospital
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