A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice
A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice
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DOI：
10.1073/pnas.0810599106
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发表时间：
2009-04-21
影响因子：
11.1
通讯作者：
Davies, Kay E.
中科院分区：
文献类型：
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作者：
Becker, Esther B. E.;Olivera, Peter L.;Davies, Kay E.
遗传性共济失调是一组复杂的神经系统疾病，其特征在于小脑及其相关连接的变性。在这组疾病中触发浦肯野细胞损失的分子机制仍不完全清楚。在这里，我们报告了一个以前未描述的显性小脑共济失调，月球漫步（Mwk），显示运动和协调缺陷和小脑浦肯野细胞的损失小鼠模型。Mwk小鼠在编码非选择性瞬时受体电位阳离子通道C3（TRPC 3）的Trpc 3基因中存在功能获得性突变（T635A），导致TRPC 3通道门控改变。TRPC 3在树突状细胞发生阶段在浦肯野细胞中高度表达。有趣的是，Mwk小鼠浦肯野细胞树突状细胞的生长和分化严重受损。我们的研究结果定义了TRPC 3在树突发育和浦肯野细胞存活中的一个先前未知的作用，并提供了小脑共济失调的一个独特机制。
The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.