Distinct behavioral and neuropathological abnormalities in transgenic mouse models of HD and DRPLA

Huntington's disease (HD) and Dentatorubral and pallidoluysian atrophy (DRP LA) are autosomal dominant, neurodegenerative disorders caused by the expan sion of polyglutamine tracts in their respective proteins, huntingtin and a trophin-1. We have previously generated mouse models of these disorders, us ing transgenes expressed via the prion protein promoter. Here, we report th e first direct comparison of abnormalities in these models. The Ho mice sho w abbreviated lifespans (4-6 months), hypoactivity, and mild impairment of motor skills. The DRPLA mice show severe tremors, are hyperactive, and are profoundly uncoordinated. Neuropathological analyses reveal that the distri bution of diffuse nuclear immunolabeling and neuronal intranuclear inclusio ns (NII's), in the CNS of both models, was remarkably similar. Cytoplasmic aggregates of huntingtin were the major distinguishing neuropathological fe ature of the Ho mice; mutant atrophin-1 accumulated/aggregated only in the nucleus. We suggest that the distinct behavioral and neuropathological phen otypes in these mice reflect differences in the way these mutant proteins p erturb neuronal function. (C) 2001 Academic Press.