The Center for Brain Integration Research and Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8519, Japan.
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17693-8. doi: 10.1073/pnas.1212786109. Epub 2012 Oct 10.
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Ca(v)2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Ca(v)2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.
脊髓小脑共济失调 6 型（SCA6）是一种由 Ca(v)2.1 电压门控钙通道中谷氨酸盐重复扩展引起的神经退行性疾病。为了阐明这个质膜蛋白中扩展的多聚谷氨酰胺链如何导致疾病，我们创建了一个独特的基因敲入小鼠模型，该模型在内源性启动子的控制下适度过表达突变转录本（MPI-118Q）。MPI-118Q 小鼠忠实地再现了 SCA6 的许多特征，包括浦肯野细胞的选择性退化。令人惊讶的是，对突变浦肯野细胞中包涵体形成的分析表明，在没有自噬反应的情况下，积累的突变 Ca(v)2.1 通道定位于溶酶体。溶酶体天冬氨酸蛋白水解酶 B（一种主要的溶酶体半胱氨酸蛋白酶）的缺乏加剧了浦肯野细胞的丧失，并伴随着该模型中包涵体形成的加速。因此，SCA6 的发病机制涉及内溶酶体降解途径，而该模型的独特病理特征进一步说明了蛋白质结构在多聚谷氨酰胺疾病发病机制中的关键作用。
