Rona K Graham1, Yu Deng2, Mahmoud A Pouladi3, Kuljeet Vaid2, Dagmar Ehrnhoefer2, Amber L Southwell2, Nagat Bissada2, Sonia Franciosi2, Michael R Hayden2. 1. Research Center on Aging, Department of Physiology and Biophysics, University of Sherbrooke, Sherbrooke, QC, Canada. 2. Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. 3. 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.
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 AND METHODS: 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.
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 AND METHODS: 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 HDmouse 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/C6Rmice 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/C6Rmice 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: Niels H Skotte; Shaun S Sanders; Roshni R Singaraja; Dagmar E Ehrnhoefer; Kuljeet Vaid; Xiaofan Qiu; Srinivasaragavan Kannan; Chandra Verma; Michael R Hayden Journal: Cell Death Differ Date: 2016-12-02 Impact factor: 15.828
Authors: Dagmar E Ehrnhoefer; Dale D O Martin; Mandi E Schmidt; Xiaofan Qiu; Safia Ladha; Nicholas S Caron; Niels H Skotte; Yen T N Nguyen; Kuljeet Vaid; Amber L Southwell; Sabine Engemann; Sonia Franciosi; Michael R Hayden Journal: Acta Neuropathol Commun Date: 2018-03-06 Impact factor: 7.801