Authors: Van Raamsdonk, Jeremy M.¹; Pearson, Jacqueline¹; Rogers, Daniel A.¹; Bissada, Nagat¹; Vogl, A. Wayne²; Hayden, Michael R.¹; Leavitt, Blair R.¹

Source: Human Molecular Genetics, Volume 14, Number 10, 15 May 2005 , pp. 1379-1392(14)

Publisher: Oxford University Press

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.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/ddi147

Affiliations: 1: Department of Medical Genetics, 2: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 and

Publication date: 2005-05-15

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• Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.

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• By this author: Van Raamsdonk, Jeremy M. ;  Pearson, Jacqueline ;  Rogers, Daniel A. ;  Bissada, Nagat ;  Vogl, A. Wayne ;  Hayden, Michael R. ;  Leavitt, Blair R.

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