Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels

K Watase, CF Barrett, T Miyazaki… - Proceedings of the …, 2008 - National Acad Sciences
K Watase, CF Barrett, T Miyazaki, T Ishiguro, K Ishikawa, Y Hu, T Unno, Y Sun, S Kasai…
Proceedings of the National Academy of Sciences, 2008National Acad Sciences
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by CAG
repeat expansions within the voltage-gated calcium (CaV) 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 (KI) mice carrying
normal, expanded, or hyperexpanded CAG repeat tracts in the Cacna1a locus. The mice …
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by CAG repeat expansions within the voltage-gated calcium (CaV) 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 (KI) mice carrying normal, expanded, or hyperexpanded CAG repeat tracts in the Cacna1a locus. The mice expressing hyperexpanded polyglutamine (Sca684Q) developed progressive motor impairment and aggregation of mutant CaV2.1 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 Sca684Q 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 CaV2.1 channels.
National Acad Sciences