A two-hit hypothesis for dystonia pathophysiology: Cerebello-thalamo-striatal dysfunction and connectivity in DYT1 mice

摘要 肌张力障碍是一种神经发育疾病，其特征是不自主的扭转运动。有效肌张力障碍 治疗方法仍然难以捉摸，因为导致并持续运动异常的功能失调的回路(S) 在很大程度上是没有特征的。促进我们对肌张力障碍的病理生理学和 开发新的治疗策略是缺乏基于病因学的动物模型 类似肌张力障碍的行为。我们通过设计一种表现出强健运动的小鼠模型克服了这一限制。 在肌张力障碍基因TOR1A.TorsinA中断后，青少年发育开始的异常， 由TOR1A组成的蛋白质在大脑发育过程中对于突触的形成和丢失是重要的 导致功能连接异常。我将使用我们的新的小鼠模型来研究扭力A的丧失 大脑运动回路的功能会导致肌张力障碍。我将测试一个新观点：肌张力障碍是由连续的侮辱造成的。 首先，基因突变会导致一小群关键的神经元进行异常的解剖连接。 然后，持续的回路功能障碍会加强异常运动。这些研究之所以成为可能，是因为 我的实验室创造了多种独特设计的工具和先进的脑成像方法 在德克萨斯大学西南分校开发，研究将在那里进行。这项建议还将推进我们的 通过识别传播和抑制运动所需的脑回路变化来理解肌张力障碍 功能障碍。这一认识将为今后旨在开发有效的肌张力障碍治疗方法的工作提供指导。

ABSTRACT Dystonia is neurodevelopmental disease characterized by involuntary twisting movements. Effective dystonia treatments remain elusive because the dysfunctional circuit(s) that cause and perpetuate the motor abnormalities is largely uncharacterized. One limitation to advancing our understanding of dystonia pathophysiology and developing novel therapeutic strategies is the lack of etiologically based animal models that exhibit overt dystonia-like behaviors. We overcame this limitation by engineering a mouse model that exhibits robust motor abnormalities starting in juvenile development, following a disruption of the dystonia gene, TOR1A.TorsinA, the protein that is made from the TOR1A, is important during brain development for synaptogenesis and its loss results in abnormal functional connectivity. I will use our novel mouse model to investigate how a loss of torsinA function in brain motor circuits causes dystonia. I will test a new idea: that dystonia results from sequential insults. First, genetic mutations cause a small but critical group of neurons to make aberrant anatomical connections. Then, sustained circuit dysfunction reinforces abnormal movements. These studies are possible because of multiple uniquely designed “tools" my lab has created and the advanced brain imaging methods that have been developed at UT Southwestern, where the study will be performed. This proposal will also advance our understanding of dystonia by identifying the brain circuit changes required to propagate and suppress motor dysfunction. This understanding will inform future work aimed at developing effective therapies for dystonia.