Human Molecular Genetics, 1999, Vol. 8, No. 7 1185-1193
© 1999 Oxford University Press
Abundant expression and cytoplasmic aggregations of 
1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6
1Department of Neurology and 2Department of Pharmacology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan, 3Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan, 4CREST, Japan Science and Technology Corp., Japan, 5Department of Neurology, Tokyo Metropolitan Neurological Hospital, Fuchu-shi, Tokyo, Japan, 6Department of Internal Medicine, Hatsuishi Hospital, Kashiwa-shi, Chiba, Japan and 7Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Spinocerebellar ataxia type 6 (SCA6) is one of the eight neurodegenerative diseases caused by a trinucleotide (CAG) repeat expansion coding polyglutamine (CAG repeat/polyglutamine diseases) and is characterized by late onset autosomal dominant cerebellar ataxia and predominant loss of cerebellar Purkinje cells. Although the causative, small and stable CAG repeat expansion for this disease has been identified in the 
1A voltage-dependent calcium channel gene (CACNA1A), the mechanism which leads to predominant Purkinje cell degeneration is totally unknown. In this study, we show that the calcium channel mRNA/protein containing the CAG repeat/polyglutamine tract is most intensely expressed in Purkinje cells of human brains. In SCA6 brains, numerous oval or rod-shaped aggregates were seen exclusively in the cytoplasm of Purkinje cells. These cytoplasmic inclusions were not ubiquitinated, which contrasts with the neuronal intranuclear inclusions of other CAG repeat/polyglutamine diseases. In cultured cells, formation of perinuclear aggregates of the channel protein and apoptotic cell death were seen when transfected with full-length CACNA1A coding an expanded polyglutamine tract. The present study indicates that the mechanism of neurodegeneration in SCA6 is associated with cytoplasmic aggregations of the 1A calcium channel protein caused by a small CAG repeat/polyglutamine expansion in CACNA1A.
a To whom correspondence should be addressed at: Department of Neurology, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, 113-8519, Tokyo, Japan. Tel: +81 03 5803 5233; Fax: +81 03 5803 0134; Email: h-mizusawa.nuro{at}med.tmd.ac.jp
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