Nat Genet 13 (4): 442-449 (Aug 1996)

Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract

Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Bromm M, Kazemi-Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

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 CAG expansion. Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis.

MeSH Terms:

• Animal
• Apoptosis*
• Cell Line
• Cercopithecus aethiops
• Cysteine Proteinases/metabolism*
• Human
• Huntington's Disease/physiopathology
• Kinetics
• Nerve Tissue Proteins/metabolism*
• Nuclear Proteins/metabolism*
• Peptides/chemistry
• Recombinant Proteins
• Structure-Activity Relationship
• Substrate Specificity
• Support, Non-U.S. Gov't
• Transfection
• Trinucleotide Repeats

Substances:

• polyglutamine
• Recombinant Proteins
• Peptides
• Nuclear Proteins
• Nerve Tissue Proteins
• Huntingtin protein
• CPP32 protein
• Cysteine Proteinases

PMID: 8696339, MUID: 96331285