Generation of Mouse Models for Early Onset Dystonia

早发性肌张力障碍是一种常染色体显性遗传性运动障碍，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，然而我们最近描述了一个相同基因18个碱基对缺失的家系。肌张力障碍的发病机制(S)仍不清楚，但S的缺陷被认为累及基底节，证据来自多种形式的肌张力障碍，以及最近从PO1获得的数据，表明多巴胺能代谢的改变参与了肌张力障碍的发病机制。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，以探索疾病的机制。在上一个周期中，我们创造了在强启动子(CMV)控制下过表达野生型(Wt)或Gag缺失(Delta E)突变的转基因(TG)动物。 初步结果表明，这些小鼠在旋转棒上的测试中，在运动学习方面存在缺陷。此外，我们已经培育出四环素诱导的双基因小鼠，它们在正在评估的神经元中特异性地表达wt或gag缺失。在这项应用中，我们将使用这些模型并产生额外的转基因动物来确定DYT1基因产物的正常功能，以及疾病是由 功能。此外，我们将通过选择性敲击或在多巴胺能神经元中过度表达DYT1基因来探讨多巴胺能系统是否参与了DYT1肌张力障碍的发病。在这个项目中产生的所有小鼠都将接受神经学和运动表型的评估，并在发育(项目2)和成年(项目1)期间接受神经化学和神经病理分析。这些小鼠还将用于测试遗传修饰物。 这些小鼠的产生应该会导致关于这种基因(DYT1)功能的线索，并最终找到可行的治疗这种疾病的方法。

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.