title: Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin.
abstract: Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HD, we generated YAC mice expressing caspase-3- and caspase-6-resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis and excitotoxicity in HD.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Slow
authors.forename: Brendan
authors.initials: B
authors.lastname: Haigh
authors.forename: Nagat
authors.initials: N
authors.lastname: Bissada
authors.forename: Ge
authors.initials: G
authors.lastname: Lu
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Pearson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Shehadeh
authors.forename: Lisa
authors.initials: L
authors.lastname: Bertram
authors.forename: Zoe
authors.initials: Z
authors.lastname: Murphy
authors.forename: Simon C
authors.initials: SC
authors.lastname: Warby
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Doty
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
authors.forename: Donald W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053178:Caspase 6; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D006868:Hydrolysis; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016202:N-Methylaspartate / Q000633:toxicity; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017378:Quinolinic Acid / Q000633:toxicity; D019311:Staurosporine / Q000633:toxicity
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016202:N-Methylaspartate; C505514:CASP6 protein, human; C505516:Casp6 protein, mouse; D053178:Caspase 6; D020169:Caspases; D017378:Quinolinic Acid; D019311:Staurosporine