Spinocerebellar ataxia type 6: Lessons from faithful knock-in mouse models.n mouse models.
Spinocerebellar ataxia type 6: Lessons from faithful knock-in mouse models.n mouse models.
复制标题
脊髓小脑共济失调 6 型：来自忠实敲入小鼠模型的教训。n 小鼠模型。
DOI：
10.1111/ncn3.137
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发表时间：
2015
影响因子：
0.4
通讯作者：
Kei Watase
中科院分区：
文献类型：
--
作者：
Hatanaka Y.;Watase K.;Wada K.;Nagai Y.;藤山文乃;Kei Watase
6 型脊髓小脑性共济失调是一种显性遗传性神经退行性疾病，其特征是缓慢进行性共济失调、言语不清和眼球震颤。 6 型脊髓小脑共济失调的分子发病机制引起了相当多的关注，因为它是由 Cav2.1 电压门控 Ca++ 通道内编码多聚谷氨酰胺束的 CAG 三核苷酸重复序列的小幅扩展引起的。为了重现 6 型脊髓小脑共济失调的特征，我们培育了几个在 Cacna1 基因座中携带正常或突变 CAG 重复束的敲入小鼠品系。表达过度扩张的聚谷氨酰胺 (Sca684Q) 的小鼠出现迟发性进行性运动障碍，并在小脑浦肯野细胞的细胞质中形成神经元包涵体。 Sca684Q浦肯野细胞的电生理分析表明，重复扩张并不影响通道的内在特性。 MPI-118Q 敲入小鼠由于插入剪接位点突变而以适度增强的水平表达过度扩张的通道，概括了 6 型脊髓小脑共济失调的许多特征，包括选择性浦肯野细胞变性。对细胞质神经元内含物的分析显示了累积的突变型 Cav2.1 通道的溶酶体定位。组织蛋白酶 B（一种主要的溶酶体半胱氨酸蛋白酶）的缺乏增加了浦肯野细胞的损失，并伴随着该模型中神经元包涵体形成的加速。这些结果表明，脊髓小脑共济失调 6 型突变通过与年龄依赖性扩展的聚谷氨酰胺蛋白积累相关的机制发挥其神经毒性，并且脊髓小脑共济失调 6 型的发病机制涉及内溶酶体降解途径。
Spinocerebellar ataxia type 6 is a dominantly inherited neurodegenerative disorder characterized by slowly progressive ataxia, slurred speech and nystagmus. The molecular pathogenesis of spinocerebellar ataxia type 6 has attracted considerable attention, because it is caused by the small expansion of a CAG trinucleotide repeat encoding a polyglutamine tract within the Cav2.1 voltage‐gated Ca++channel. To recreate the characteristics of spinocerebellar ataxia type 6, we produced several lines of knock‐in mice carrying normal or mutant CAG repeat tracts in theCacna1alocus. The mice expressing a hyperexpanded polyglutamine (Sca684Q) developed late‐onset progressive motor impairment and neuronal inclusion formation in the cytoplasm of cerebellar Purkinje cells. The electrophysiological analysis of theSca684QPurkinje cells showed that the repeat expansion did not affect the intrinsic properties of the channel. MPI‐118Q knock‐in mice, which expressed a hyperexpanded channel at modestly enhanced levels because of the insertion of a splice‐site mutation, recapitulated many features of spinocerebellar ataxia type 6, including selective Purkinje cell degeneration. An analysis of the cytoplasmic neuronal inclusions showed the lysosomal localization of accumulated mutant Cav2.1 channels. The lack of cathepsin B, a major lysosomal cysteine proteinase, increased the loss of the Purkinje cells and was accompanied by an acceleration of neuronal inclusion formation in this model. These results suggest that the spinocerebellar ataxia type 6 mutation exerts its neurotoxicity through a mechanism associated with age‐dependent accumulation of the expanded polyglutamine protein, and the pathogenesis of spinocerebellar ataxia type 6 involves the endolysosomal degradation pathway.