Generation of Mouse Models for Early Onset Dystonia

早发性肌体张力障碍是一种常染色体显性遗传的运动障碍，外显率降低（30-40%）。大多数病例是由DYT1 （TOR1A）基因的3个碱基对缺失引起的，但我们最近描述了一个家族在该基因中有18个碱基对缺失。肌张力障碍的机制尚不清楚，但这种缺陷被认为与基底神经节有关，来自多种形式的肌张力障碍的证据以及来自该PO1的最新数据表明，肌张力障碍的发病机制中多巴胺能代谢的改变。随着DYT1基因的发现，我们现在可以建立针对这种疾病的小鼠模型来探索疾病的机制。在上一个周期中，我们已经创建了转基因（tg）动物，这些动物在强启动子（CMV）的控制下过表达野生型（wt）或GAG缺失（δ E）突变。

Early onset torsin dystonia is a movement disorder inherited in an autosomal dominant manner with reduced penetrance (30-40%). Most cases of the disease are caused by a 3 base pair deletion in the DYT1 (TOR1A) gene however we have recently described a family with an 18 base pair deletion in this same gene. The mechanism(s) underlying dystonia remain elusive however the defect(s) is thought to involve the basal ganglia with evidence from multiple forms of dystonia as well as more recent data from this PO1 implicating alterations in dopaminergic metabolism in the pathogenesis of dystonia. With the discovery of the DYT1 gene, we can now generate mouse models specific to this disorder to explore the mechanism of disease. In the previous cycle, we have created transgenic (tg) animals that overexpress either the wild-type (wt) or GAG deletion (delta E) mutation under the control of a strong promoter (CMV). Preliminary results suggest that these mice have a defect in motor learning as tested on the rotorod. In addition, we have produced tetracycline inducible bigenic mice that express either the wt or GAG deletion specifically in neurons that are being assessed. In this application, we will use these models and generate additional genetically modified animals to determine the normal function of the DYT1 gene product and whether the disease is caused by a gain or loss of function. In addition, we will address whether the dopaminergic system is involved in DYT1 dystonia by selectively knocking-ont or over-expressing the DYT1 gene in dopaminergic neurons. All mice generated in this Project will be evaluated for neurologic and motoric phenotypes and undergo neurochemical and neuropathological analyses during development (Project 2) and adulthood (Project 1). The mice will also be available for testing genetic modifiers discovered in Project 3. The generation of these mice should lead to clues about the function of this gene (DYT1) and eventually to viable therapies for this disease.