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

摘要 肌张力障碍是一种以不自主扭转运动为特征的神经发育性疾病。有效肌张力障碍 治疗仍然是难以捉摸的，因为引起和延续运动异常的功能障碍性回路（一个或多个 很大程度上没有特征。一个限制，以促进我们的理解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， 肌张力障碍样行为我们通过设计一种表现出强大运动能力的小鼠模型来克服这一限制 在青少年发育中开始的异常，在肌张力障碍基因TOR1A.TorsinA破坏后， 由TOR1A产生的蛋白质，在大脑发育过程中对于突触发生及其丧失非常重要 导致功能连接异常。我将使用我们的新型小鼠模型来研究如何减少扭转A 大脑运动回路的功能会导致肌张力障碍。我将测试一个新的想法：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部分关键的神经元产生异常的解剖学连接。 然后，持续的回路功能障碍强化了异常运动。这些研究之所以可行，是因为 我的实验室创造了多种独特设计的“工具”， 开发在UT西南，在那里的研究将进行。这一建议也将推动我们的 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未来旨在开发肌张力障碍有效疗法的工作提供信息。

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.