Spinocerebellar Ataxia Type 6: Lessons From Faithful Knock-In Mouse Models

Spinocerebellar ataxia type 6 is a dominantly inherited neurodegenerative disorder characterized by slowly progressive ataxia, slurred speech and nystagmus. The molecular pathogenesis of spinocerebellar ataxia type 6 has attracted considerable attention, because it is caused by the small expansion of a CAG trinucleotide repeat encoding a polyglutamine tract within the Ca(v)2.1 voltage-gated Ca++ channel. To recreate the characteristics of spinocerebellar ataxia type 6, we produced several lines of knock-in mice carrying normal or mutant CAG repeat tracts in the Cacna1a locus. The mice expressing a hyperexpanded polyglutamine (Sca6(84Q)) developed late-onset progressive motor impairment and neuronal inclusion formation in the cytoplasm of cerebellar Purkinje cells. The electrophysiological analysis of the Sca6(84Q) Purkinje cells showed that the repeat expansion did not affect the intrinsic properties of the channel. MPI-118Q knock-in mice, which expressed a hyperexpanded channel at modestly enhanced levels because of the insertion of a splice-site mutation, recapitulated many features of spinocerebellar ataxia type 6, including selective Purkinje cell degeneration. An analysis of the cytoplasmic neuronal inclusions showed the lysosomal localization of accumulated mutant Cav2.1 channels. The lack of cathepsin B, a major lysosomal cysteine proteinase, increased the loss of the Purkinje cells and was accompanied by an acceleration of neuronal inclusion formation in this model. These results suggest that the spinocerebellar ataxia type 6 mutation exerts its neurotoxicity through a mechanism associated with age-dependent accumulation of the expanded polyglutamine protein, and the pathogenesis of spinocerebellar ataxia type 6 involves the endolysosomal degradation pathway.