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Neurobiol Dis. 2015 Apr;76:24-36. doi: 10.1016/j.nbd.2014.12.030. Epub 2015 Jan 9.

Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice.

Author information

1
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.
2
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.
3
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.
4
Genzyme, a Sanofi Company, Framingham, MA 01701, USA.
5
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.
6
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.

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.

KEYWORDS:

Autophagy; Caspase-6; Huntington Disease; YAC128; p62

PMID:
25583186
DOI:
10.1016/j.nbd.2014.12.030
[Indexed for MEDLINE]

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