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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
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© 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.


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