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 TOR1A gene. Mutations in TOR1A cause early onset torsion 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. TorsinA is implicated in membrane trafficking and recycling in several cell types including neurons. Brain development relies critically on membrane trafficking and recycling events. The proposed experiments will test the hypothesis that torsinA plays critical roles in CNS development. 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 mechanism. 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 and dopaminergic imbalance, the proposed experiments will focus on the development of the basal ganglia. The experiments will use wild type and transgenic mice, and will proceed in two stages. First, the regional and cellular distribution of torsinA will be examined in the embryonic and early postnatal brains using western blot and immunohistochemical methods. The goal of these studies is to understand if the expression of the proteins is developmentally regulated at regional or cellular levels. Second, transgenic mice that express mutant TORIA gene or that have deletions of the TOR1A gene will be used as loss or gain of function models to study the role of TOR1A in specific developmental processes such as neurogenesis, neuronal migration, axon growth and synaptogenesis. 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.
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