Skip Navigation



Human Molecular Genetics Advance Access published online on September 23, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi340
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/20/3065    most recent
ddi340v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Benn, C. L.
Right arrow Articles by Bates, G. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Benn, C. L.
Right arrow Articles by Bates, G. P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received July 15, 2005
Revised September 7, 2005
Accepted September 7, 2005

Article

Contribution of Nuclear and Extranuclear PolyQ to Neurological Phenotypes in Mouse Models of Huntington's Disease

Caroline L. Benn 1, Christian Landles 2, He Li 3, Andrew D. Strand 4, Ben Woodman 2, Kirupa Sathasivam 2, Shi-Hua Li 3, Shabnam Ghazi-Noori 2, Emma Hockly 2, Syed M.N.N. Faruque 5, Jang-Ho J. Cha 6, Paul T. Sharpe 5, James M. Olson 4, Xiao-Jiang Li 3, and Gillian P. Bates 7*

1 King's College London, Medical and Molecular Genetics, GKT School of Medicine, London SE1 9RT, UK; MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA
2 King's College London, Medical and Molecular Genetics, GKT School of Medicine, London SE1 9RT, UK
3 Department of Genetics, Emory University, Atlanta, GA 30322, USA
4 Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA
5 Kings College London, Craniofacial Development, Dental School, London SE1 9RT, UK
6 MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA
7 King's College London, Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK

* To whom correspondence should be addressed.
Gillian P. Bates, E-mail: gillian.bates{at}genetics.kcl.ac.uk


  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 (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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 JCBHome page
C.-E. Wang, H. Zhou, J. R. McGuire, V. Cerullo, B. Lee, S.-H. Li, and X.-J. Li
Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin
J. Cell Biol., October 20, 2008; 181(5): 803 - 816.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. L. Benn, T. Sun, G. Sadri-Vakili, K. N. McFarland, D. P. DiRocco, G. J. Yohrling, T. W. Clark, B. Bouzou, and J.-H. J. Cha
Huntingtin Modulates Transcription, Occupies Gene Promoters In Vivo, and Binds Directly to DNA in a Polyglutamine-Dependent Manner
J. Neurosci., October 15, 2008; 28(42): 10720 - 10733.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. C. Warby, C. N. Doty, R. K. Graham, J. B. Carroll, Y.-Z. Yang, R. R. Singaraja, C. M. Overall, and M. R. Hayden
Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus
Hum. Mol. Genet., August 1, 2008; 17(15): 2390 - 2404.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
M. Gray, D. I. Shirasaki, C. Cepeda, V. M. Andre, B. Wilburn, X.-H. Lu, J. Tao, I. Yamazaki, S.-H. Li, Y. E. Sun, et al.
Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice
J. Neurosci., June 11, 2008; 28(24): 6182 - 6195.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
U. Bichelmeier, T. Schmidt, J. Hubener, J. Boy, L. Ruttiger, K. Habig, S. Poths, M. Bonin, M. Knipper, W. J. Schmidt, et al.
Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3: In Vivo Evidence
J. Neurosci., July 11, 2007; 27(28): 7418 - 7428.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
E. Rockabrand, N. Slepko, A. Pantalone, V. N. Nukala, A. Kazantsev, J. L. Marsh, P. G. Sullivan, J. S. Steffan, S. L. Sensi, and L. M. Thompson
The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis
Hum. Mol. Genet., January 1, 2007; 16(1): 61 - 77.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Cornett, L. Smith, M. Friedman, J.-Y. Shin, X.-J. Li, and S.-H. Li
Context-dependent Dysregulation of Transcription by Mutant Huntingtin
J. Biol. Chem., November 24, 2006; 281(47): 36198 - 36204.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.