A role for cerebellum in the hereditary dystonia DYT1
A role for cerebellum in the hereditary dystonia DYT1
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DOI：
10.7554/elife.22775
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发表时间：
2017-02-15
期刊：
影响因子：
7.7
通讯作者：
Khodakhah, Kamran
中科院分区：
文献类型：
--
作者：
Fremont, Rachel;Tewari, Ambika;Khodakhah, Kamran
DYT1 是一种由 torsinA 功能丧失突变引起的衰弱性运动障碍。这些突变如何导致肌张力障碍仍不清楚。胚胎靶向torsinA的小鼠模型未能重现患者中所见的肌张力障碍，这可能是由于啮齿类动物和人类之间的发育代偿差异所致。为了解决这个问题，使用 shRNA 在成年小鼠的特定大脑区域中急剧敲除 torsinA。 Torsin 小脑中的敲低，但基底神经节中的敲低，足以诱发肌张力障碍。与啮齿动物中 torsinA 丢失的潜在发育补偿一致，未成熟小脑中 torsinA 的敲低未能产生肌张力障碍。基因敲低动物的异常运动症状与小脑输出不规则有关，小脑输出不规则是由浦肯野细胞和小脑深核神经元的内在活动变化引起的。这些数据确定小脑是 DYT1 功能障碍的主要部位，并提供了新的治疗靶点。
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, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown 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. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets.