4.7 Article

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

Journal

NEUROBIOLOGY OF DISEASE
Volume 76, Issue -, Pages 24-36

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.12.030

Keywords

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

Categories

Funding

  1. Canadian Institutes of Health Research [CIHR] [84438]
  2. Ripples of Hope Pfizer award for Mental Health
  3. Michael Smith Foundation for Health Research [postdoctoral award]
  4. Genzyme, Sanofi company
  5. Canadian Institutes of Health Research [postdoctoral fellowship]
  6. Canadian Institutes of Health Research [doctoral award]

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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 HIT 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 HIT 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. (C) 2015 Elsevier Inc. All rights reserved.

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