Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice
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 t...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-04-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115000029 |
| id |
doaj-93e64c557c8447099a3caa50455f7c0b |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Bibiana K.Y. Wong Dagmar E. Ehrnhoefer Rona K. Graham Dale D.O. Martin Safia Ladha Valeria Uribe Lisa M. Stanek Sonia Franciosi Xiaofan Qiu Yu Deng Vlad Kovalik Weining Zhang Mahmoud A. Pouladi Lamya S. Shihabuddin Michael R. Hayden |
| spellingShingle |
Bibiana K.Y. Wong Dagmar E. Ehrnhoefer Rona K. Graham Dale D.O. Martin Safia Ladha Valeria Uribe Lisa M. Stanek Sonia Franciosi Xiaofan Qiu Yu Deng Vlad Kovalik Weining Zhang Mahmoud A. Pouladi Lamya S. Shihabuddin Michael R. Hayden Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice Neurobiology of Disease Caspase-6 YAC128 Huntington Disease Autophagy p62 |
| author_facet |
Bibiana K.Y. Wong Dagmar E. Ehrnhoefer Rona K. Graham Dale D.O. Martin Safia Ladha Valeria Uribe Lisa M. Stanek Sonia Franciosi Xiaofan Qiu Yu Deng Vlad Kovalik Weining Zhang Mahmoud A. Pouladi Lamya S. Shihabuddin Michael R. Hayden |
| author_sort |
Bibiana K.Y. Wong |
| title |
Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice |
| title_short |
Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice |
| title_full |
Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice |
| title_fullStr |
Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice |
| title_full_unstemmed |
Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice |
| title_sort |
partial rescue of some features of huntington disease in the genetic absence of caspase-6 in yac128 mice |
| publisher |
Elsevier |
| series |
Neurobiology of Disease |
| issn |
1095-953X |
| publishDate |
2015-04-01 |
| description |
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. |
| topic |
Caspase-6 YAC128 Huntington Disease Autophagy p62 |
| url |
http://www.sciencedirect.com/science/article/pii/S0969996115000029 |
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| _version_ |
1724208257074987008 |
| spelling |
doaj-93e64c557c8447099a3caa50455f7c0b2021-03-22T12:42:27ZengElsevierNeurobiology of Disease1095-953X2015-04-01762436Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 miceBibiana K.Y. Wong0Dagmar E. Ehrnhoefer1Rona K. Graham2Dale D.O. Martin3Safia Ladha4Valeria Uribe5Lisa M. Stanek6Sonia Franciosi7Xiaofan Qiu8Yu Deng9Vlad Kovalik10Weining Zhang11Mahmoud A. Pouladi12Lamya S. Shihabuddin13Michael R. Hayden14Centre 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, USACentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre 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, CanadaCentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaGenzyme, a Sanofi Company, Framingham, MA 01701, USACentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, CanadaCentre 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, SingaporeGenzyme, a Sanofi Company, Framingham, MA 01701, USACentre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Corresponding author. Fax: +1 604 875 3819.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.http://www.sciencedirect.com/science/article/pii/S0969996115000029Caspase-6YAC128Huntington DiseaseAutophagyp62 |