Functional Analysis of TorsinA

描述（由申请人提供）： 早发性扭转性肌张力障碍是遗传性肌张力障碍中最常见和最严重的形式。这种疾病的许多病例与蛋白质torsinA中的单个氨基酸缺失有关。TorsinA是一种在内质网中发现的AAA+ ATP酶，但其正常细胞功能和在肌张力障碍发病机制中的作用尚不清楚。本项目的目标是确定由torsinA控制的细胞和分子事件，以便开始了解这种难以捉摸的疾病的病因。在初步研究中，我们使用了在培养细胞中表达的torsinA突变体，并确定了torsinA在ER的一个亚结构域（核膜）中的可能功能。本提案中的实验将探索torsinA如何作为AAA+ ATP酶发挥作用，并定义其在核膜中的确切作用。 我们的具体目标是： 1.开发和实验测试torsinA功能的结构模型，然后将其应用于了解疾病相关突变如何影响蛋白质功能。 2.研究torsinA在内质网和核膜中的动态和分布，以验证核膜是其主要作用部位的假设。 3.明确扭转蛋白A在核膜中的分子靶点。

DESCRIPTION (provided by applicant): 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.