Contributions of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease.

Caroline Benn, C Landles, H Li, A D Strand, B Woodman, K Sathasivam, S H Li, S Ghazi-Noori, E Hockly, S M N N Faruque, J H J Cha, P T Sharpe, J M Olson, X J Li, G P Bates

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102 Citations (Scopus)

Abstract

In postmortem Huntington's disease brains, mutant htt is present in both nuclear and cytoplasmic compartments. 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 or nuclear export signal sequences 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 suggest that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression
Original languageEnglish
Pages (from-to)3065 - 3078
Number of pages14
JournalHuman Molecular Genetics
Volume14
Issue number20
DOIs
Publication statusPublished - Oct 2005

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