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Human Molecular Genetics Advance Access originally published online on September 23, 2005
Human Molecular Genetics 2005 14(20):3065-3078; doi:10.1093/hmg/ddi340
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Caroline L. Benn1,5, Christian Landles1, He Li2, Andrew D. Strand3, Ben Woodman1, Kirupa Sathasivam1, Shi-Hua Li2, Shabnam Ghazi-Noori1, Emma Hockly1, Syed M.N.N. Faruque4, Jang-Ho J. Cha5, Paul T. Sharpe4, James M. Olson3, Xiao-Jiang Li2 and Gillian P. Bates1,*

1King's College London, Medical and Molecular Genetics, GKT School of Medicine, London SE1 9RT, UK, 2Department of Genetics, Emory University, Atlanta, GA 30322, USA, 3Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA, 4King's College London, Craniofacial Development, Dental School, London SE1 9RT, UK and 5MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA

* To whom correspondence should be addressed at: King's College London, Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. Tel: +44 2071883722; Fax: +44 2071882585; Email: gillian.bates{at}genetics.kcl.ac.uk

Received July 15, 2005; Accepted September 7, 2005

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.


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