Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Cav2.1 channels
Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Cav2.1 channels
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DOI：
10.1073/pnas.0804350105
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发表时间：
2008-08-19
影响因子：
11.1
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Watase, Kei;Barrett, Curtis F.;Zoghbi, Huda Y.
脊髓小脑性共济失调 6 型 (SCA6) 是一种神经退行性疾病，由电压门控钙 (Ca-v) 2.1 通道基因内的 CAG 重复扩张引起。该突变是否通过改变 Ca(v)2.1 通道的功能或通过与扩展的聚谷氨酰胺蛋白的积累相关的功能获得机制来发挥神经毒性，仍存在争议。我们生成了三种敲入 (KI) 小鼠品系，它们在 Cacna1a 基因座中携带正常、扩增或超扩增的 CAG 重复序列。表达过度扩张的聚谷氨酰胺 (Sca6(84Q)) 的小鼠出现进行性运动障碍和突变 Ca(v)2.1 通道聚集。小脑浦肯野细胞的电生理分析显示，三种 KI 模型的 Ca2(+) 通道电流密度相似。 Sca6(84Q) 神经元中激活和失活的电压敏感性均未改变，这表明扩大的 CAG 重复本身不会影响通道的内在电生理特性。 SCA6 的发病机制显然与年龄依赖性过程有关，并伴有突变 Ca(v)2.1 通道的积累。
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by CAG repeat expansions within the voltage-gated calcium (Ca-v) 2.1 channel gene. It remains controversial whether the mutation exerts neurotoxicity by changing the function of Ca(v)2.1 channel or through a gain-of-function mechanism associated with accumulation of the expanded polyglutamine protein. We generated three strains of knockin (KI) mice carrying normal, expanded, or hyperexpanded CAG repeat tracts in the Cacna1a locus. The mice expressing hyperexpanded polyglutamine (Sca6(84Q)) developed progressive motor impairment and aggregation of mutant Ca(v)2.1 channels. Electrophysiological analysis of cerebellar Purkinje cells revealed similar Ca2(+) channel current density among the three KI models. Neither voltage sensitivity of activation nor inactivation was altered in the Sca6(84Q) neurons, suggesting that expanded CAG repeat per se does not affect the intrinsic electrophysiological properties of the channels. The pathogenesis of SCA6 is apparently linked to an age-dependent process accompanied by accumulation of mutant Ca(v)2.1 channels.