The polyglutamine expansion in spinocerebellar ataxia type 6 causes a betasubunit-specific enhanced activation of P/Q-type calcium channels in Xenopus oocytes

Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited degenerative disorder of the cerebellum characterized by nearly selective and progressi ve death of Purkinje cells. The underlying mutation in SCA6 consists of an expansion of a trinucleotide CAG repeat in the 3' region of the gene, CACNA 1A, encoding the alpha(1A) subunit of the neuronal P/Q-type voltage-gated c alcium channel. Although it is known that this mutation results in an expan ded tract of glutamine residues in some alpha(1A) splice forms, the distrib ution of these splice forms and the role of this mutation in the highly sel ective Purkinje cell degeneration seen in SCA6 have yet to be elucidated. U sing specific antisera we demonstrate that the pathological expansion in SC A6 can potentially be expressed in multiple isoforms of the alpha(1A) subun it, and that these isoforms are abundantly expressed in the cerebellum, par ticularly in the Purkinje cell bodies and dendrites. Using alpha(1A) subuni t chimeras expressing SCA6 mutations, we show that the SCA6 polyglutamine e xpansion shifts the voltage dependence of channel activation and rate of in activation only when expressed with beta(4) subunits and impairs normal G-p rotein regulation of P/Q channels. These findings suggest the possibility t hat SCA6 is a channelopathy, and that the underlying mutation in SCA6 cause s Purkinje cell degeneration through excessive entry of calcium ions.