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

描述（由申请人提供）：DYT 1肌张力障碍是一种神经发育疾病，由编码torsinA的Tor 1a基因缺失（Δ gag; Δ E）引起。虽然这种突变是在1997年发现的，但目前还不清楚E突变是否通过功能机制的获得或丧失而导致异常运动。混淆这个问题，目前还不清楚何时E突变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促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个基于torsinA的小鼠模型，该模型会产生明显的异常运动。在这个应用程序中，我们描述了第一个这样的模型与公开的肌张力障碍样扭转运动的发展。此外，我们已经开发了一套相关的基于torsinA的小鼠模型，这将使我们能够在发育或成熟的CNS中删除torsinA或诱导β-torsinA的内源性表达。我们基于这些模型的广泛的初步数据已经使我们能够做出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，提供了肌张力障碍发病机制的机制见解。我们建议使用这些新的模型1）定义导致异常运动的β E突变的机制; 2）确定在神经发育过程中何时发生关键事件; 3）测试以下假设：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DYT 1肌张力障碍。

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.