title: Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease.
abstract: 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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, British Columbia Children's and Women's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: Danny
authors.initials: D
authors.lastname: Rogers
authors.forename: Simon
authors.initials: S
authors.lastname: Warby
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Odell
authors.initials: O
authors.lastname: Loubser
authors.forename: Jeremy
authors.initials: J
authors.lastname: van Raamsdonk
authors.forename: Roshni
authors.initials: R
authors.lastname: Singaraja
authors.forename: Yu-Zhou
authors.initials: YZ
authors.lastname: Yang
authors.forename: Juliette
authors.initials: J
authors.lastname: Gafni
authors.forename: Dale
authors.initials: D
authors.lastname: Bredesen
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hersch
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Donald W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000918:Antibody Specificity; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D018244:Chromosomes, Artificial, Yeast; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D014162:Transfection; D019680:Trinucleotide Repeat Expansion
chemical_list: D000906:Antibodies; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D020169:Caspases