Becker Esther B E, Oliver Peter L, Glitsch Maike D, Banks Gareth T, Achilli Francesca, Hardy Andrea, Nolan Patrick M, Fisher Elizabeth M C, Davies Kay E
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom.
Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6706-11. doi: 10.1073/pnas.0810599106. Epub 2009 Apr 7.
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.
遗传性共济失调是一组复杂的神经系统疾病，其特征是小脑及其相关连接发生退化。引发这类疾病中浦肯野细胞丧失的分子机制仍未完全明确。在此，我们报告一种先前未被描述的小脑共济失调显性小鼠模型——月行者（Mwk），该模型表现出运动和协调缺陷以及小脑浦肯野细胞丧失。Mwk小鼠在编码非选择性瞬时受体电位阳离子通道C3型（TRPC3）的Trpc3基因中存在功能获得性突变（T635A），导致TRPC3通道门控改变。TRPC3在树突形成阶段的浦肯野细胞中高度表达。有趣的是，Mwk小鼠中浦肯野细胞树突分支的生长和分化受到严重损害。我们的研究结果确定了TRPC3在浦肯野细胞树突发育和存活中以前未知的作用，并提供了小脑共济失调的独特机制。
