Pathophysiology of DYT1 Dystonia: Targeted Mouse Models

描述(申请人提供)：奥本海姆肌张力障碍是一种全身性早发性肌张力障碍。这是一种常染色体显性遗传病，由于3-碱基缺失(AGAG)导致DYT1编码区的谷氨酸残基缺失，导致外显性降低。目前还不知道TorsinA蛋白在细胞中起什么作用，更不用说突变的TorsinA蛋白如何导致肌张力障碍的机制了。广泛的、长期的目标是使用转基因小鼠来确定：1)TorsinA在体内的功能作用是什么？2)TorsinA突变蛋白是如何导致早发性肌张力障碍的？此应用程序的目的是分析我们创建的DYT1 Agag敲入小鼠，以测试DYT1 Agag突变是一种功能缺失或功能减退突变的假设，该突变扰乱皮质纹状体通路的多巴胺能调制，进而导致对运动和姿势的异常控制。在这里，我们建议检验DYT1 Agag突变导致功能丧失或降低，而不是毒性功能获得的假设，我们将确定三个野生型(WT)和突变型torsinA蛋白水平改变的转基因小鼠的相对运动表现、神经化学、神经病理学和电生理学。我们将确定在突变torsinA存在的情况下，不同水平的WT torsinA蛋白是否会改变突变小鼠的运动行为、神经化学、神经病理学和电生理学。此外，为了验证DYT1 Agag突变破坏多巴胺能功能特别是D2受体途径的假设，我们将测量和比较DYT1 Agag敲击型和野生型小鼠多巴胺能系统的各个方面。这些研究将加深对正常TorsinA的功能、突变型TorsinA在肌张力障碍的病理生理学中的作用以及突变型TorsinA引起神经干扰的机制的了解。有了这种理解，就可以设计出新的创造性的治疗方法来对抗DYT1肌张力障碍引起的虚弱症状。

DESCRIPTION (provided by applicant): Oppenheim's dystonia is a generalized early-onset dystonia. It is an autosomal dominant disorder with reduced penetrance due to a 3-bp deletion (AGAG) that deletes a glutamic acid residue in the coding region of DYT1, which codes for torsinA protein. It is not known what functions torsinA protein serves in the cell, let alone mechanisms of how the mutant torsinA protein could lead to dystonia. The broad, long-term objective is to use transgenic mice to determine: 1) what is the functional role of torsinA in vivo? 2) How does the mutant torsinA protein lead to early onset dystonia? The objective of this application is to analyze Dyt1 AGAG knock-in mice that we have created to test the hypotheses that DYT1 AGAG mutation is a loss- or reduction-of-function mutation that disrupts dopaminergic modulation of corticostriatal pathway, which in turn leads to an abnormal control of movement and posture. Here we propose to test the hypothesis that DYT1 AGAG mutation leads to a loss- or reduction-of-function, and not a toxic gain-of-function, we will determine the relative motor performance, neurochemistry, neuropathology, and electrophysiology of three lines of transgenic mice with altered level of wild-type (WT) and mutant torsinA proteins. We will determine if varying levels of WT torsinA protein in the presence of a mutant torsinA alter mutant mice's motor behaviors, neurochemistry, neuropathology and electrophysiology. Furthermore, to test the hypothesis that Dyt1 AGAG mutation disrupts dopaminergic function especially D2 receptor pathway, we will measure and compare the various aspects of the dopaminergic system in Dyt1 AGAG knockin and wild-type mice. These studies will increase the understanding about the function of normal torsinA, the role of mutant torsinA in the pathophysiology of dystonia, and the mechanism through which the neural interference is caused by mutant torsinA. With this understanding, new and creative therapies can be devised to combat the debilitating symptoms caused by DYT1 dystonia.