SCA1 TRANSGENIC MICE - A MODEL FOR NEURODEGENERATION CAUSED BY AN EXPANDED CAG TRINUCLEOTIDE REPEAT

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherite d disorder characterized by degeneration of cerebellar Purkinje cells, spinocerebellar tracts, and selective brainstem neurons owing to the expansion of an unstable CAG trinucleotide repeat. To gain insight int o the pathogenesis of the SCA1 mutation and the intergenerational stab ility of trinucleotide repeats in mice, we have generated transgenic m ice expressing the human SCA1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent to offspring transmi ssions. While all six transgenic lines expressing the unexpanded human SCA1 allele had normal Purkinje cells, transgenic animals from five o f six lines with the expanded SCA1 allele developed ataxia and Purkinj e cell degeneration. These data indicate that expanded CAG repeats exp ressed in Purkinje cells are sufficient to produce degeneration and at axia and demonstrate that a mouse model can be established for neurode generation caused by CAG repeat expansions.