Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca_v2.1 channels

摘要

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 Cav2.1 channel or through a gain-of-function mechanism associated with accumulation of the expanded polyglutamine protein. We generated three strains of knockin (Kl) mice carrying normal, expanded, or hyperexpanded CAG repeat tracts in the Cacnaia locus. The mice expressing hyperexpanded polyglutamine (Sca6~(84Q)) developed progressive motor impairment and aggregation of mutant Ca_v2.1 channels. Electrophysiological analysis of cerebellar Purkinje cells revealed similar Ca~(2+) channel current density among the three Kl 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_v2.1 channels.