Contribution of Nuclear and Extranuclear PolyQ to Neurological Phenotypes in Mouse Models of Huntington’s Disease. Mus musculus

To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization (NLS) or nuclear export sequences (NES) have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for, and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggests that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression. Keywords: Trangenic mouse brain gene expression Overall design: Five lines of transgenic mice and normal littermate controls were compared using Affymetrix MG-U74Av2 A arrays to examine gene expression in cerebellum. Each line had 3 or 4 replicates. Profiles were made at the first age that rotorod deficits could be detected. Some lines were also profiled at a later age when neurological impairment was more pronounced.