Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus

To elucidate the pathophysiology of spinocerebellar ataxia type 1 (SCA1) an d to evaluate repeat length instability in the context of the mouse Sca1 ge ne, we generated knock-in mice by inserting an expanded tract of 78 CAG rep eats into the mouse Sca1 locus, Mice heterozygous for the CAG expansion sho w intergenerational repeat instability (+2 to -6) at a much higher frequenc y in maternal transmission than in paternal transmission. The majority of c hanges transmitted through the female germline were small contractions, as in humans, whereas small expansions occurred more frequently in paternal tr ansmission. The frequency of intergenerational changes was age dependent fo r both paternal and maternal transmissions. Mice homozygous for mutant atax in-1 on a C57BL/6J-129/SvEv mixed background performed significantly less w ell on the rotating rod than did wild-type littermates at 9 months of age, although they were not ataxic by cage behavior. Histological examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathological changes observed in other transgenic models overexpressin g expanded polyglutamine tracts. These data suggest that, even with 78 glut amines, prolonged exposure to mutant ataxin-1 at endogenous levels is neces sary to produce a neurological phenotype reminiscent of human SCA1, Pathoge nesis is thus a function of polyglutamine length, protein levels and durati on of neuronal exposure to the mutant protein.