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

Spinocerebellar ataxia type 6 (SCA6) is one of the eight neurodegenerative diseases caused by a trinucleotide (CAG) repeat expansion coding polyglutam ine (CAG repeat/polyglutamine diseases) and is characterized by late onset autosomal dominant cerebellar ataxia and predominant loss of cerebellar Pur kinje cells. Although the causative, small and stable CAG repeat expansion for this disease has been identified in the al A voltage-dependent calcium channel gene (CACNA1A), the mechanism which leads to predominant Purkinje c ell degeneration is totally unknown. In this study, we show that the calciu m channel mRNA/protein containing the CAG repeat/polyglutamine tract is mos t intensely expressed in Purkinje cells of human brains. In SCA6 brains, nu merous oval or rod-shaped aggregates were seen exclusively in the cytoplasm of Purkinje cells. These cytoplasmic inclusions were not ubiquitinated, wh ich contrasts with the neuronal intranuclear inclusions of other CAG repeat /polyglutamine diseases. In cultured cells, formation of perinuclear aggreg ates of the channel protein and apoptotic cell death were seen when transfe cted with full-length CACNA1A coding an expanded polyglutamine tract. The p resent study indicates that the mechanism of neurodegeneration in SCA6 is a ssociated with cytoplasmic aggregations of the alpha 1A calcium channel pro tein caused by a small CAG repeat/polyglutamine expansion in CACNA1A.