Journal Article

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

Caroline L. Benn, Christian Landles, He Li, Andrew D. Strand, Ben Woodman, Kirupa Sathasivam, Shi-Hua Li, Shabnam Ghazi-Noori, Emma Hockly, Syed M.N.N. Faruque, Jang-Ho J. Cha, Paul T. Sharpe, James M. Olson, Xiao-Jiang Li and Gillian P. Bates

in Human Molecular Genetics

Volume 14, issue 20, pages 3065-3078
Published in print October 2005 | ISSN: 0964-6906
Published online September 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi340
Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease

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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.

Journal Article.  9788 words.  Illustrated.

Subjects: Genetics and Genomics

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