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Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

Dagmar E Ehrnhoefer1, Niels H Skotte1, Jeanette Reinshagen2

  • 1Centre for Molecular Medicine and Therapeutics (CMMT), Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.

Cell Chemical Biology
|July 30, 2019
PubMed

Insights

Aberrant caspase-6 (C6) activation drives Huntington disease (HD) pathogenesis. A C6-cleaved fragment of mutant huntingtin (mHTT) stabilizes C6, creating a self-amplifying cycle that a novel inhibitor can disrupt.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Aberrant caspase-6 (C6) activation occurs in Huntington disease (HD) without typical apoptosis hallmarks.
  • C6 activity correlates with HD progression, and cleavage of mutant huntingtin (mHTT) is implicated in pathogenesis.

Purpose of the Study:

  • To investigate the mechanism by which C6 contributes to HD pathogenesis.
  • To identify potential therapeutic targets for disrupting the C6-mHTT interaction.

Main Methods:

  • Biochemical assays to study C6 and mHTT interactions.
  • Molecular docking to analyze inhibitor binding.
  • Cellular and animal models of Huntington disease.

Main Results:

  • The mHTT1-586 fragment generated by C6 cleavage interacts with C6 zymogen.
  • This interaction stabilizes an active conformation of C6, promoting further activation.
  • A small-molecule inhibitor blocks the C6-mHTT1-586 interaction, preventing enhanced C6 activity.

Conclusions:

  • The interaction between mHTT1-586 and C6 zymogen forms a feedforward loop, driving HD pathogenesis.
  • Inhibiting this interaction offers a potential therapeutic strategy for Huntington disease.

Keywords:
Huntington diseaseallostericcaspase-6inhibitornon-apoptotic

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