Pathophysiology of DYT1 Dystonia: Targeted Mouse Models

描述（由申请人提供）：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疾病，由于3-bp缺失（AGAG）导致DNA多态性降低，该缺失了DYT 1编码区的谷氨酸残基，DYT 1编码torsinA蛋白。目前尚不清楚torsinA蛋白在细胞中的功能，更不用说突变体torsinA蛋白如何导致肌张力障碍的机制了。广泛的长期目标是使用转基因小鼠来确定：1）扭转蛋白A在体内的功能作用是什么？2)突变型torsinA蛋白如何导致早发性肌张力障碍？本申请的目的是分析Dyt 1 AGAG基因敲入小鼠，我们已经创建了测试的假设，即DYT 1 AGAG突变是一种功能丧失或减少突变，破坏皮质纹状体通路的多巴胺能调节，这反过来又导致异常控制的运动和姿势。在这里，我们建议测试的假设，DYT 1 AGAG突变导致的损失或减少的功能，而不是一个有毒的功能获得，我们将确定相对运动性能，神经化学，神经病理学和电生理学的三个线的转基因小鼠与野生型（WT）和突变体torsinA蛋白水平改变。我们将确定在突变型torsinA存在下，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，为了检验Dyt 1 AGAG突变破坏多巴胺能功能特别是D2受体通路的假设，我们将测量和比较Dyt 1 AGAG敲入小鼠和野生型小鼠中多巴胺能系统的各个方面。这些研究将增加对正常torsinA的功能、突变torsinA在肌张力障碍的病理生理学中的作用以及突变torsinA引起神经干扰的机制的理解。有了这种理解，新的和创造性的疗法可以设计出来，以打击由DYT 1肌张力障碍引起的衰弱症状。

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.