Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease.
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.
Van Raamsdonk
Jeremy M
JM
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Pearson
Jacqueline
J
Rogers
Daniel A
DA
Bissada
Nagat
N
Vogl
A Wayne
AW
Hayden
Michael R
MR
Leavitt
Blair R
BR
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013737:Testis / Q000378:metabolism / Q000473:pathology
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins