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

Huntington's disease (HD) and Dentatorubral and pallidoluysian atrophy (DRPLA) are autosomal dominant, neurodegenerative disorders caused by the expansion of polyglutamine tracts in their respective proteins, huntingtin and atrophin-1. We have previously generated mouse models of these disorders, using transgenes expressed via the prion protein promoter. Here, we report the first direct comparison of abnormalities in these models. The HD mice show 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 distribution of diffuse nuclear immunolabeling and neuronal intranuclear inclusions (NII's), in the CNS of both models, was remarkably similar. Cytoplasmic aggregates of huntingtin were the major distinguishing neuropathological feature of the HD mice; mutant atrophin-1 accumulated/aggregated only in the nucleus. We suggest that the distinct behavioral and neuropathological phenotypes in these mice reflect differences in the way these mutant proteins perturb neuronal function.