Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels.
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 Ca(2+) 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.
Watase
Kei
K
Twenty-First Century Center of Excellence Program on Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Barrett
Curtis F
CF
Miyazaki
Taisuke
T
Ishiguro
Taro
T
Ishikawa
Kinya
K
Hu
Yuanxin
Y
Unno
Toshinori
T
Sun
Yaling
Y
Kasai
Sayumi
S
Watanabe
Masahiko
M
Gomez
Christopher M
CM
Mizusawa
Hidehiro
H
Tsien
Richard W
RW
Zoghbi
Huda Y
HY
D000375:Aging / Q000502:physiology*; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism*; D018450:Disease Progression; D004594:Electrophysiology; D005091:Exons / Q000235:genetics; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019076:Transgenes / Q000235:genetics
D020864:Calcium Channels, N-Type; D050505:Mutant Proteins