title: Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice.
abstract: Huntington Disease (HD) is a progressive neurodegenerative disease caused by an elongated CAG repeat in the huntingtin (HTT) gene that encodes a polyglutamine tract in the HTT protein. Proteolysis of the mutant HTT protein (mHTT) has been detected in human and murine HD brains and is implicated in the pathogenesis of HD. Of particular importance is the site at amino acid (aa) 586 that contains a caspase-6 (Casp6) recognition motif. Activation of Casp6 occurs presymptomatically in human HD patients and the inhibition of mHTT proteolysis at aa586 in the YAC128 mouse model results in the full rescue of HD-like phenotypes. Surprisingly, Casp6 ablation in two different HD mouse models did not completely prevent the generation of this fragment, and therapeutic benefits were limited, questioning the role of Casp6 in the disease. We have evaluated the impact of the loss of Casp6 in the YAC128 mouse model of HD. Levels of the mHTT-586 fragment are reduced but not absent in the absence of Casp6 and we identify caspase 8 as an alternate enzyme that can generate this fragment. In vivo, the ablation of Casp6 results in a partial rescue of body weight gain, normalized IGF-1 levels, a reversal of the depression-like phenotype and decreased HTT levels. In the YAC128/Casp6-/- striatum there is a concomitant reduction in p62 levels, a marker of autophagic activity, suggesting increased autophagic clearance. These results implicate the HTT-586 fragment as a key contributor to certain features of HD, irrespective of the enzyme involved in its generation.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bibiana K Y
authors.initials: BKY
authors.lastname: Wong
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Dagmar E
authors.initials: DE
authors.lastname: Ehrnhoefer
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Research Center on Aging, Department of Physiology and Biophysics, University of Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Dale D O
authors.initials: DDO
authors.lastname: Martin
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Safia
authors.initials: S
authors.lastname: Ladha
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Valeria
authors.initials: V
authors.lastname: Uribe
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Stanek
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Franciosi
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Vlad
authors.initials: V
authors.lastname: Kovalik
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Weining
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, 138648, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 138648, Singapore.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.affiliation: Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. Electronic address: mrh@cmmt.ubc.ca.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D001835:Body Weight; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D053178:Caspase 6 / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D003863:Depression / Q000378:metabolism; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000201:enzymology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D007334:Insulin-Like Growth Factor I; D053178:Caspase 6
keywords: Autophagy; Caspase-6; Huntington Disease; YAC128; p62