Watase Kei, Ishikawa Kinya, Mizusawa Hidehiro
Center for Brain Integration Research, Tokyo Medical and Dental University.
Rinsho Shinkeigaku. 2010 Nov;50(11):858-60. doi: 10.5692/clinicalneurol.50.858.
Spinocerebellar ataxia type 6 (SCA6) is one of the common dominantly inherited ataxias in Japan, featuring late-onset ataxia and selective Purkinje cell (PC) degeneration. Molecular pathogenesis of SCA6 has been attracting considerable attention since it is caused by small CAG repeat expansions within the Ca(v)2.1 voltage-gated Ca(++) channel gene (CACNA1A). During the past 9 years, efforts have been made to generate and analyze a precise SCA6 model in order to disclose its molecular pathogenesis in vivo. Evidence indicates that the SCA6 mutation does not directly change the basic properties of the channel but rather exerts neurotoxicity through a mechanism associated with age-dependent accumulation of the expanded polyglutamine protein. We envisage further analysis on a knockin model developing PC degeneration at their young age will lead to elucidation of the molecular pathways involved in SCA6 and thus be useful for developing therapeutic strategies against the disease.
6型脊髓小脑共济失调（SCA6）是日本常见的显性遗传性共济失调之一，其特征为迟发性共济失调和选择性浦肯野细胞（PC）变性。SCA6的分子发病机制一直备受关注，因为它是由Ca（v）2.1电压门控钙通道基因（CACNA1A）内的小CAG重复序列扩增引起的。在过去9年中，人们努力构建并分析精确的SCA6模型，以揭示其体内分子发病机制。有证据表明，SCA6突变不会直接改变通道的基本特性，而是通过与扩增的多聚谷氨酰胺蛋白的年龄依赖性积累相关的机制发挥神经毒性作用。我们设想，对在年轻时发生PC变性的基因敲入模型进行进一步分析，将有助于阐明SCA6所涉及的分子途径，从而有助于开发针对该疾病的治疗策略。
