Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of Ca _V2.1 Ca ²⁺ channela - 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 Ca _V2.1 (P/Q-type) Ca ²⁺ channel α ₁2.1 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 Ca ²⁺ channel α ₁2.1 subunit cDNA and expressed them in baby hamster kidney cells stably expressing the auxiliary subunits (α ₂δ and β ₄). The occurrence of cell death differed between cells transfected with the normal and mutant Ca ²⁺ channels under the condition of serum starvation plus potassium-induced depolarization, and Cdk inhibition elucidated the differences more clearly. The Ca _V2.1 (P/Q-type) Ca ²⁺ channel-specific blocker ω-agatoxin IVA abolished the cell-death-preventing effect of the normal Ca ²⁺ channel. Together with our previous finding that the polyglutamine expansion in SCA6 interferes with the Ca ²⁺ channel to reduce Ca ²⁺ influx, these results indicate that impaired function of the mutant Ca ²⁺ channels rendered them unable to prevent cell death.