Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease.
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.
Wellington
Cheryl L
CL
Centre for Molecular Medicine and Therapeutics, British Columbia Children's and Women's Hospital, Vancouver, British Columbia, Canada.
Ellerby
Lisa M
LM
Gutekunst
Claire-Anne
CA
Rogers
Danny
D
Warby
Simon
S
Graham
Rona K
RK
Loubser
Odell
O
van Raamsdonk
Jeremy
J
Singaraja
Roshni
R
Yang
Yu-Zhou
YZ
Gafni
Juliette
J
Bredesen
Dale
D
Hersch
Steven M
SM
Leavitt
Blair R
BR
Roy
Sophie
S
Nicholson
Donald W
DW
Hayden
Michael R
MR
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
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