Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of CaV2.1 Ca2+ channel--loss-of-function cellular model of SCA6.

Spinocerebellar ataxia (SCA) 6 is caused by small expansion of a polyglutamine sequence, encoded by CAG trinucleotide repeats, at the C-terminal end of the human CaV2.1 (P/Q-type) Ca2+ channel alpha12.1 subunit and it manifests itself as slowly progressive cerebellar ataxia. To elucidate the pathogenic mechanisms underlying SCA6, we introduced CAG repeats of various lengths into the Ca2+ channel alpha12.1 subunit cDNA and expressed them in baby hamster kidney cells stably expressing the auxiliary subunits (alpha2delta and beta4). The occurrence of cell death differed between cells transfected with the normal and mutant Ca2+ channels under the condition of serum starvation plus potassium-induced depolarization, and Cdk inhibition elucidated the differences more clearly. The CaV2.1 (P/Q-type) Ca2+ channel-specific blocker omega-agatoxin IVA abolished the cell-death-preventing effect of the normal Ca2+ channel. Together with our previous finding that the polyglutamine expansion in SCA6 interferes with the Ca2+ channel to reduce Ca2+ influx, these results indicate that impaired function of the mutant Ca2+ channels rendered them unable to prevent cell death.