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

• Published in: Human molecular genetics 2005-05, Vol.14 (10), p.1379-1392
• Main Authors: Van Raamsdonk, Jeremy M., Pearson, Jacqueline, Rogers, Daniel A., Bissada, Nagat, Vogl, A. Wayne, Hayden, Michael R., Leavitt, Blair R.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - physiology; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - mortality; Huntington Disease - physiopathology; Male; Medical sciences; Mice; Molecular and cellular biology; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurology; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Testis - metabolism; Testis - pathology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi147

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