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 Ca(V)2.1 (P/Q-type) Ca2+ channel alpha(1)2.1 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 alpha(1)2.1 subunit cDNA and expressed them in baby hamster kidney cells stably expressing the auxiliary subunits (alpha(2)delta and beta(4)). 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 Ca(V)2.1 (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. (C) 2004 Elsevier Inc. All rights reserved.