? Early onset torsion dystonia is the most common and severe form of inherited dystonia. Many cases of this disease are associated with a single amino acid deletion in the protein torsinA. TorsinA is an AAA+ ATPase found in the endoplasmic reticulum, but its normal cellular function and role in the pathogenesis of dystonia are unknown. The goal of this project is to define cellular and molecular events controlled by torsinA in order to begin to understand the etiology of this elusive disease. In preliminary studies, we used torsinA mutants expressed in cultured cells and identified a likely function for torsinA in a subdomain of the ER, the nuclear envelope. Experiments in this proposal will explore how torsinA functions as an AAA+ ATPase and define its exact role in the nuclear envelope. ? Our specific aims are: ? 1. To develop and experimentally test a structural model for torsinA function, and then apply this to understanding how disease-linked mutations affect protein function. ? 2. To study torsinA dynamics and distribution in the endoplasmic reticulum and nuclear envelope to test the hypothesis that the nuclear envelope is its primary site of action. ? 3. To define the molecular targets of torsinA in the nuclear envelope. ? ?
