title: Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels.
abstract: 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.
authors.affiliation: 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.
authors.forename: Kei
authors.initials: K
authors.lastname: Watase
authors.forename: Curtis F
authors.initials: CF
authors.lastname: Barrett
authors.forename: Taisuke
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Taro
authors.initials: T
authors.lastname: Ishiguro
authors.forename: Kinya
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Hu
authors.forename: Toshinori
authors.initials: T
authors.lastname: Unno
authors.forename: Yaling
authors.initials: Y
authors.lastname: Sun
authors.forename: Sayumi
authors.initials: S
authors.lastname: Kasai
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gomez
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsien
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: 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
chemical_list: D020864:Calcium Channels, N-Type; D050505:Mutant Proteins