TorsinA function and dystonia-related dysfunction in developing and mature CNS

描述（由申请人提供）：DYT1肌张力障碍是一种由编码torsinA的Tor1a基因缺失（¿gag；¿E）引起的神经发育疾病。虽然这种突变是在1997年发现的，但目前尚不清楚¿E突变是否通过功能的获得或丧失机制导致异常运动。令人困惑的是，目前还不清楚基因突变何时会破坏运动系统的发育和功能。这些问题在概念上和实践上都很重要，因为迫切需要它们的答案来推进对肌张力障碍发病机制的理解，并开始设计合理的靶向治疗（例如，知道torsinA功能丧失导致异常运动将建议寻找torsinA激活化合物）。解开导致肌张力障碍的¿E突变机制的一个主要障碍是缺乏一种基于肌体的小鼠模型，这种模型会产生明显的异常运动。在这个应用中，我们描述了第一个具有明显的动力样扭曲运动的模型的发展。此外，我们开发了一套相关的基于torsinA的小鼠模型，使我们能够在发育或成熟的中枢神经系统中删除torsinA或诱导¿E-torsinA的内源性表达。我们基于这些模型的大量初步数据已经使我们能够进行一系列令人兴奋的观察，将¿E突变，torsinA功能丧失，运动电路选择性分子病理学和异常扭转运动联系起来。这些数据还确定了torsinA同源物torsinB作为torsinA表型的强大调节剂，为肌张力障碍的发病机制提供了深入的了解。我们建议使用这些新模型：1)定义导致异常运动的¿E突变的机制；2)确定神经发育过程中关键事件发生的时间；3)验证torsinB是CNS对torsinA功能障碍敏感性的关键决定因素，可用于抑制或预防DYT1肌张力障碍的假设。

DESCRIPTION (provided by applicant): 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.