We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease.
- Authors
Van Raamsdonk, Jeremy M.; Pearson, Jacqueline; Rogers, Daniel A.; Bissada, Nagat; Vogl, A. Wayne; Hayden, Michael R.; Leavitt, Blair R.
- 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 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.
- Publication
Human Molecular Genetics, 2005, Vol 14, Issue 10, p1379
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddi147