A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration

We have produced yeast artificial chromosome (YAC) transgenic mice expressi ng normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a develo pmental and tissue-specific manner identical to that observed in Huntington 's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnor malities, indicating cytoplasmic dysfunction prior to observed nuclear incl usions or neurodegeneration. By 12 months of age, YAC72 mice have a selecti ve degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodeg eneration can be present in the absence of macro- or microaggregates, clear ly showing that aggregates are not essential to initiation of neuronal deat h. These mice demonstrate that initial neuronal cytoplasmic toxicity is fol lowed by cleavage of htt, nuclear translocation of htt N-terminal fragments , and selective neurodegeneration.