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Human Molecular Genetics Advance Access published online on April 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi147
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 1, 2005
Revised April 4, 2005
Accepted April 4, 2005

Article

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

Jeremy M Van Raamsdonk 1, Jacqueline Pearson 1, Daniel A. Rogers 1, Nagat Bissada 1, A. Wayne Vogl 2, Michael R. Hayden 1*, and Blair R. Leavitt 1

1 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada, V6T 1Z3; Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute, 980 West 28th Avenue, Vancouver, B.C., Canada, V5Z 4H4
2 Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3

* To whom correspondence should be addressed.
Michael R. Hayden, E-mail: mrh{at}cmmt.ubc.ca


  Abstract

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 to YAC128 +/+ mice at 2 months (p=0.003). Striatal neuropathology was not clearly worse in YAC128 -/- mice compared to 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 to WT mice which was exacerbated by the loss of wild type htt (12 month male survival, p<0.001). Overall, we demonstrate that 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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