Brain regions and genes implicated in early onset dystonia

虽然导致DYT1肌张力障碍的基因在近十年前就被发现，但其机制 对这种或许多其他形式的肌张力障碍患者的症状负有责任仍不确定。这是 这是合理设计有效疗法的主要障碍。在之前的支持期间，我们制作了 并描述了几种表达异常扭蛋白A的DYT1小鼠模型 大脑中的蛋白质，并发现这些蛋白质既表现出行为上的，也表现出神经化学上的 看起来与人类疾病相似的异常现象。这些都提供了重要的 洞察突变型torsinA对大脑功能的影响。然而，这些模型并不能解决 异常蛋白如何导致表型异常的问题，或确定作用部位的问题。在……里面 本项目，我们将生产和研究一系列新型的选择性失活Torsin A的小鼠模型， 或敲入DYT1突变。使用这些，我们将解决以下问题：选择性失活在 大脑皮质、纹状体或小脑足以产生行为和神经化学异常。 完整的啮齿动物。鉴于许多形式的肌张力障碍涉及基底节的有力证据，我们 将通过检查DYT1突变的选择性失活或敲击来进一步缩小焦点 纹状体神经元群，以及多巴胺能神经元内。该项目还将与 其他项目和核心，以确定开发其他新型鼠标模型的机会。最后，我们会 寻求通过评估已知对人类有效的药物治疗的效果来验证这些模型 肌张力障碍，并建立国家资源这些模式的分发，以促进发展 新奇的疗法。这项工作的总体目标是建立关节的解剖位置和机制。 功能障碍是DYT1和其他肌张力障碍的罪魁祸首，并能够对这种疾病进行靶向治疗。

Although the gene which causes DYT1 dystonia was discovered nearly a decade ago, the mechanism responsible for the symptoms in patients with this or many other forms of dystonia remains uncertain. This is a major obstacle to the rational design of effective therapies. During the prior period of support, we produced and characterized several mouse models of DYT1 in which there is expression of the abnormal torsinA protein throughout the brain, and found that these exhibit both behavioral as well as neurochemical abnormalities which appear to resemble aspects ofthe human disease. These have provided important insight into the effects of mutant torsinA on brain function. These models do not, however, resolve the question of how the abnormal protein leads to the phenotypic abnormalities, or identify the site of action. In this project, we will produce and study a novel series of mouse models with selective inactivation of torsinA, or knock-in ofthe DYT1 mutation. Using these, we will address the issue of whether selective inactivation in the cortex, striatum, or cerebellum is sufficient to produce behavioral and neurochemical abnormalities in the intact rodent. Given the strong evidence for involvement of the basal ganglia in many forms of dystonia, we will narrow the focus further by examining selective inactivation or knock-in ofthe DYT1 mutation in populations of striatal neurons, and within dopaminergic neurons. This project will also work closely with the other projects and cores, to identify opportunities to develop additional novel mouse models. Finally, we will seek to validate these models by assessing the effect of a drug treatment known to be effective in human dystonia, and establish a National Resource for distribution of these models to promote development of novel therapies. The overall goal of this work is to establish the anatomical site and mechanism of the dysfunction responsible for DYT1 and other dystonias, and enable targeted therapies for the disease.