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Previous Article | Next Article
The Journal of Neuroscience, September 15, 2002, 22(18):7862-7872
Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease
Cheryl L. Wellington1, Lisa M. Ellerby2, Claire-Anne Gutekunst3, Danny Rogers1, Simon Warby1, Rona K. Graham1, Odell Loubser1, Jeremy van Raamsdonk1, Roshni Singaraja1, Yu-Zhou Yang1, Juliette Gafni2, Dale Bredesen2, Steven M. Hersch4, Blair R. Leavitt1, Sophie Roy5, Donald W. Nicholson5, and Michael R. Hayden1 1 Centre for Molecular Medicine and Therapeutics, British Columbia Children's and Women's Hospital, Vancouver, British Columbia, Canada V5Z 4H4, 2 Buck Institute for Research in Aging, Novato, California 94945, 3 Department of Neurology, Emory University, Atlanta, Georgia 30322, 4 Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and 5 Merck Frosst Centre for Therapeutic Research, Montreal, Quebec, Canada H9R 4P8
Huntington's disease (HD) results from polyglutamine expansion in huntingtin (htt), a protein with several consensus caspase cleavage sites. Despite the identification of htt fragments in the brain, it has not been shown conclusively that htt is cleaved by caspases in vivo. Furthermore, no study has addressed when htt cleavage occurs with respect to the onset of neurodegeneration. Using antibodies that detect only caspase-cleaved htt, we demonstrate that htt is cleaved in vivo specifically at the caspase consensus site at amino acid 552. We detect caspase-cleaved htt in control human brain as well as in HD brains with early grade neuropathology, including one homozygote. Cleaved htt is also seen in wild-type and HD transgenic mouse brains before the onset of neurodegeneration. These results suggest that caspase cleavage of htt may be a normal physiological event. However, in HD, cleavage of mutant htt would release N-terminal fragments with the potential for increased toxicity and accumulation caused by the presence of the expanded polyglutamine tract. Furthermore, htt fragments were detected most abundantly in cortical projection neurons, suggesting that accumulation of expanded htt fragments in these neurons may lead to corticostriatal dysfunction as an early event in the pathogenesis of HD.
Key words: Huntington's disease; huntingtin; caspase cleavage; in vivo; corticostriatal pathway; neurodegeneration
Copyright © 2002 Society for Neuroscience 0270-6474/02/22187862-11$05.00/0
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