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Abundant expression and cytoplasmic aggregations of 1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6.

Authors: Ishikawa, K  Fujigasaki, H  Saegusa, H  Ohwada, K  Fujita, T  Iwamoto, H  Komatsuzaki, Y  Toru, S  Toriyama, H  Watanabe, M  Ohkoshi, N  Shoji, S  Kanazawa, I  Tanabe, T  Mizusawa, H 
Citation: Ishikawa K, etal., Hum Mol Genet. 1999 Jul;8(7):1185-93.
Pubmed: (View Article at PubMed) PMID:10369863

Spinocerebellar ataxia type 6 (SCA6) is one of the eight neurodegenerative diseases caused by a tri-nucleotide (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 [alpha]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 intra-nuclear 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 [alpha]1A calcium channel protein caused by a small CAG repeat/polyglutamine expansion in CACNA1A.


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RGD Object Information
RGD ID: 10054421
Created: 2015-08-05
Species: All species
Last Modified: 2015-08-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.