title: Caspase-6-Resistant Mutant Huntingtin Does not Rescue the Toxic Effects of Caspase-Cleavable Mutant Huntingtin in vivo.
abstract: BACKGROUND
  The amelioration of behavioral and neuropathological deficits in mice expressing caspase-6-resistant (C6R) mutant huntingtin (mhtt), despite the presence of an expanded polyglutamine tract, highlights proteolysis of htt at the 586aa caspase-6 (casp6) site may be an important mechanism in the pathogenesis of Huntington disease (HD). One possible explanation of these effects is that C6R mhtt could act as a dominant negative on mhtt.
  
  
  OBJECTIVE
  To determine if the neuroprotective effect observed in the C6R mice is due to dominant negative effects, we crossed the C6R mice to the YAC128 HD mouse model to generate mice expressing both caspase-cleavable and C6R mhtt (YAC/C6R) concurrently and assessed previously defined behavioral and neuropathological endpoints.
  
  
  RESULTS
  Our results demonstrate that YAC/C6R animals exhibit similar motor abnormalities and learning deficits as the YAC128 mice. Neuropathological analysis reveals a significant decrease in brain weight and striatal volume in the YAC/C6R mice comparable to the YAC128 mice. In contrast, and similar to previous findings, C6R mice demonstrate preserved brain weight and striatal volume. As expected, body weight is significantly increased in the YAC/C6R mice due to the increased levels of htt.
  
  
  CONCLUSIONS
  The results of this study suggest that the lack of an HD phenotype in the C6R mice is most likely due to the absence of cleavage of htt and not due to suppression of expression of mhtt.
authors: Research Center on Aging, Department of Physiology and Biophysics, University of Sherbrooke, Sherbrooke, QC, Canada.
authors: Rona K
authors: RK
authors: Graham
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Yu
authors: Y
authors: Deng
authors: Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Republic of Singapore Department of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors: Mahmoud A
authors: MA
authors: Pouladi
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Kuljeet
authors: K
authors: Vaid
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Dagmar
authors: D
authors: Ehrnhoefer
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Amber L
authors: AL
authors: Southwell
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Nagat
authors: N
authors: Bissada
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Sonia
authors: S
authors: Franciosi
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors: Michael R
authors: MR
authors: Hayden
mesh_terms: D000818:Animals; D053178:Caspase 6 / Q000378:metabolism*; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D013045:Species Specificity
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C505516:Casp6 protein, mouse; D053178:Caspase 6
keywords: Huntington disease; apoptosis; caspase-6; human; mouse models; mutant huntingtin