Skip Navigation


Human Molecular Genetics Advance Access originally published online on April 13, 2005
Human Molecular Genetics 2005 14(10):1379-1392; doi:10.1093/hmg/ddi147
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Material
Right arrow All Versions of this Article:
14/10/1379    most recent
ddi147v1
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 ISI Web of Science
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 arrow Search for citing articles in:
ISI Web of Science (24)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Van Raamsdonk, J. M.
Right arrow Articles by Leavitt, B. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Van Raamsdonk, J. M.
Right arrow Articles by Leavitt, B. R.
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. For Permissions, please email: journals.permissions@oupjournals.org

Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease

Jeremy M. Van Raamsdonk1,3, Jacqueline Pearson1,3, Daniel A. Rogers1,3, Nagat Bissada1,3, A. Wayne Vogl2, Michael R. Hayden1,3,* and Blair R. Leavitt1,3

1Department of Medical Genetics, 2Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 and 3Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute, Vancouver, BC, Canada V5Z 4H4

* To whom correspondence should be addressed at: Centre for Molecular Medicine and Therapeutics, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4. Tel: +1 604 875 3535; FaxL +1 604 875 3819; Email: mrh{at}cmmt.ubc.ca

Received March 1, 2005; Accepted April 4, 2005

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by a toxic gain of function in the huntingtin (htt) protein. The contribution of wild-type htt function to the pathogenesis of HD is currently uncertain. To assess the role of wild-type htt in HD, we generated YAC128 mice that do not express wild-type htt (YAC128–/–) but express the same amount of mutant htt as normal YAC128 mice (YAC128+/+). YAC128–/– mice perform worse than YAC128+/+ mice in the rotarod test of motor coordination (P=0.001) and are hypoactive compared with YAC128+/+ mice at 2 months (P=0.003). Striatal neuropathology was not clearly worse in YAC128–/– mice compared with YAC128+/+ mice. There was no significant effect of decreased wild-type htt on striatal volume, neuronal counts or DARPP-32 expression but a modest worsening of striatal neuronal atrophy was evident (6%, P=0.03). The testis of YAC128+/+ mice showed atrophy and degeneration, which was markedly worsened in the absence of wild-type htt (P=0.001). YAC128+/+ mice also showed a male specific deficit in survival compared with WT mice which was exacerbated by the loss of wild-type htt (12-month-male survival, P<0.001). Overall, we demonstrate that the loss of wild-type htt influences motor dysfunction, hyperkinesia, testicular degeneration and impaired lifespan in YAC128 mice. The mild effect of wild-type htt on striatal phenotypes in YAC128 mice suggests that the characteristic striatal neuropathology in HD is caused primarily by the toxicity of mutant htt and that replacement of wild-type htt will not be an adequate treatment for HD.


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
 J. Biol. Chem.Home page
A. L. Orr, S. Huang, M. A. Roberts, J. C. Reed, S. Li, and X.-J. Li
Sex-dependent Effect of BAG1 in Ameliorating Motor Deficits of Huntington Disease Transgenic Mice
J. Biol. Chem., June 6, 2008; 283(23): 16027 - 16036.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. L. Lumsden, T. L. Henshall, S. Dayan, M. T. Lardelli, and R. I. Richards
Huntingtin-deficient zebrafish exhibit defects in iron utilization and development
Hum. Mol. Genet., August 15, 2007; 16(16): 1905 - 1920.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. Zuccato, N. Belyaev, P. Conforti, L. Ooi, M. Tartari, E. Papadimou, M. MacDonald, E. Fossale, S. Zeitlin, N. Buckley, et al.
Widespread Disruption of Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor Occupancy at Its Target Genes in Huntington's Disease
J. Neurosci., June 27, 2007; 27(26): 6972 - 6983.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. S. Thomas Jr, G. S. Fraley, V. Damien, L. B. Woodke, F. Zapata, B. L. Sopher, S. R. Plymate, and A. R. La Spada
Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy
Hum. Mol. Genet., July 15, 2006; 15(14): 2225 - 2238.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W. Li, L. C. Serpell, W. J. Carter, D. C. Rubinsztein, and J. A. Huntington
Expression and Characterization of Full-length Human Huntingtin, an Elongated HEAT Repeat Protein
J. Biol. Chem., June 9, 2006; 281(23): 15916 - 15922.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. M. Van Raamsdonk, W. T. Gibson, J. Pearson, Z. Murphy, G. Lu, B. R. Leavitt, and M. R. Hayden
Body weight is modulated by levels of full-length Huntingtin
Hum. Mol. Genet., May 1, 2006; 15(9): 1513 - 1523.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. M. Van Raamsdonk, Z. Murphy, E. J. Slow, B. R. Leavitt, and M. R. Hayden
Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease
Hum. Mol. Genet., December 15, 2005; 14(24): 3823 - 3835.
[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.