Nature Genetics
13, 442 - 449 (1996)
doi:10.1038/ng0896-442
Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tractY.P. Goldberg1, *, D.W. Nicholson2, *, D.M. Rasper2, M.A. Kalchman1, H.B. Koide1, R.K. Graham1, M. Bromm1, P. Kazemi-Esfarjani1, N.A. Thornberry3, J.P. Vaillancourt2
& M.R. Hayden1, 4
1 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
2Department of Biochemistry and Molecular Biology, Merck Frosst, Centre for Therapeutic Research, Montreal, Quebec, Canada
3Department of Enzymology, Merck Research Laboratories, Rahway, New Jersey, USA
*Y.P.G. & D.W.N. contributed equally to this manuscript
4Correspondence should be addressed to M.R.H. Apoptosis has recently been recognized as a mode of cell death in Huntington disease (HD). Apopain, a human counterpart of the nematode cysteine protease death−gene product, CED−3, has a key role in proteolytic events leading to apoptosis. Here we show that apoptotic extracts and apopain itself specifically cleave the HD gene product, huntingtin. The rate of cleavage increases with the length of the huntingtin polyglutamine tract, providing an explanation for the gain−of−function associated with GAG expansion. Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis.
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