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Spinocerebellar ataxia type 6(SCA6) Kinya Ishikawa 1 , Hidehiro Mizusawa 1 1Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Garduate School of Medical and Dental Sciences Keyword: α1A-カルシウムチャネル , SCA6 , 脊髄小脳変性症 , Purkinje細胞 , ポリグルタミン pp.249-258
Published Date 2003/4/10
DOI https://doi.org/10.11477/mf.1431100304
  • Abstract
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 Spinocerebellar ataxia type 6(SCA6)is an autosomal dominant cerebellar ataxia caused by a small expansion of CAG repeat that encode polyglutamine in the alpha1A-voltage-dependent calcium channel gene. This disease is one of the most common dominantly-inherited ataxia in Japan. The CAG repeat ranges from 4 to 19 repeat-unit in normal Japanese population while the repeat is expanded in the range between 20 to 33 repeat-unit in patients. Cardinal clinical features are summarized as purely cerebellar ataxia in most SCA6 patients, although a variety of extracerebellar signs such as pyramidal tract signs or neuropathy, may be seen in some patients. Vertical gaze-nystagmus and oscillopsia are reported characteristic to SCA6. Neuropathologically, cerebellar cortical degeneration with predominant neuronal loss of the Purkinje cells is seen.

 Precise mechanism that leads to neurodegeneration in SCA6 remains elusive. The expression of mutant alpha1A-calcium channel gene is highest in the Purkinje cell both in the cDNA and protein levels. This may be the important basis of selective neurodegeneration in SCA6. When the mutant alpha1A-calcium channel cDNA was expressed in cultured cells, alterations of calcium channel properties were documented. This would strongly indicate that expansion of polyglutamine in the alpha1A-calcium channel protein causes neuronal dysfunction, and unltimately to neurodegeneration, by disturbing the voltage-dependent gating of calcium ion controlled by the channel protein at the plasma membrane. However, discrepancies in the way of alterations of calcium channel properties have been seen among groups studying this issue, possibly due to use of different alpha1A-calcium channel cDNAs. Therefore, identification and use of cDNAs predominantly expressed in the human Purkinje cells may be important. Finally, two types of aggregations, one is composed of alpha1A-calcium channel and the other is composed of expanded polyglutamine of unknown protein, are seen exclusively in the SCA6 Purkinje cells. This would indicate that abnormal protein aggregations take place in SCA6. Identification of mechanism causing protein aggregation may elucidate the pathogenesis of SCA6.


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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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