Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca V 2.1 channels

• DOI: 10.1073/pnas.0804350105
• Publication Date: 2008-08-08T01:25:56Z
• Authors: Kei Watase; Curtis F. Barrett; Taisuke Miyazaki; Taro Ishiguro; Kinya Ishikawa; Yuanxin Hu; Toshinori Unno; Yaling Sun; Sayumi Kasai; Masahiko Watanabe; Christopher M. Gomez; Hidehiro Mizusawa; Richard W. Tsien; Huda Y. Zoghbi
• Keywords: Wild type

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 mutation exerts neurotoxicity changing function of Ca or through gain-of-function mechanism associated with accumulation expanded polyglutamine protein. We generated three strains knockin (KI) mice carrying normal, expanded, hyperexpanded tracts in Cacna1a locus. The expressing ( Sca6 84Q developed progressive motor impairment and aggregation mutant channels. Electrophysiological analysis cerebellar Purkinje cells revealed similar 2+ current density among KI models. Neither voltage sensitivity activation nor inactivation was altered neurons, suggesting that per se does not affect intrinsic electrophysiological properties pathogenesis SCA6 apparently linked to an age-dependent process accompanied