Cerebellar Dysfunction in DYT1

摘要 DYT 1是一种由torsinA功能缺失突变引起的衰弱性运动障碍。如何将这些 突变导致肌张力障碍仍然未知。具有胚胎靶向扭转蛋白A的小鼠模型 未能概括在患者中观察到的肌张力障碍，可能是由于不同的发育 啮齿动物和人类之间的补偿。为了解决这个问题，我们开发了一种新的鼠标 模型中使用shRNA在成年小鼠的选定脑区域中急性敲除torsinA。我们 已经发现，在小脑中，而不是在基底神经节中，torsinA敲低足以诱导 肌张力障碍肌张力障碍动物的异常运动症状与不规则小脑 由浦肯野细胞和深部神经元的内在活动变化引起的输出 小脑核该提议利用DYT 1的这种张力障碍模型来探索回路、神经元， 以及分子水平上torsinA的缺失如何导致肌张力障碍。该建议基于三个具体目标。在第一个具体目标中，我们将检验以下假设： DYT 1异常小脑输出通过改变基底神经节的活动引起肌张力障碍， 丘脑双突触的Cb-BG通路，我们已经表征。具体目标2将检验假设 在小脑浦肯野细胞和/或DCN神经元中选择性敲低torsinA， 功能障碍和肌张力障碍。最后，第三个具体目标测试的假设，击倒的 torsinA改变浦肯野细胞和DCN神经元的内在起搏， 选择电导的功能。成功地实现所设定的目标将极大地促进我们对DYT 1的理解 肌张力障碍，并可能为其治疗提供有价值的潜在治疗靶点。

Abstract DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, we have developed a new mouse model where torsinA is acutely knocked down in select brain regions of adult mice using shRNAs. We have found that torsinA knockdown in the cerebellum, but not in the basal ganglia, is sufficient to induce dystonia. Abnormal motor symptoms in dystonic animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. This proposal capitalizes on this dystonic model of DYT1 to explore at circuit, neuronal, and molecular levels how loss of torsinA causes dystonia. The proposal is based on three specific aims. In the first specific aim we will test the hypothesis that in DYT1 abnormal cerebellar output causes dystonia by altering the activity of the basal ganglia via the thalamic disynaptic Cb-BG pathway that we have characterized. Specific Aim 2 will test the hypothesis that selective knock down of torsinA in cerebellar Purkinje cells and/or DCN neurons causes cerebellar dysfunction and dystonia. And lastly the third specific Aim tests the hypothesis that knock down of torsinA alters the intrinsic pacemaking of Purkinje cells and DCN neurons by altering the expression or function of select conductances. Successful accomplishment of the aims set will significantly advance our understanding of DYT1 dystonia, and may provide valuable potential therapeutic targets for its treatment.