A Huntingtin-based peptide inhibitor of caspase-6 provides protection from mutant Huntingtin-induced motor and behavioral deficits

Hum Mol Genet. 2015 May 1;24(9):2604-14. doi: 10.1093/hmg/ddv023. Epub 2015 Jan 23.


Over the past decade, increasing evidence has implied a significant connection between caspase-6 activity and the pathogenesis of Huntington's disease (HD). Consequently, inhibiting caspase-6 activity was suggested as a promising therapeutic strategy to reduce mutant Huntingtin toxicity, and to provide protection from mutant Huntingtin-induced motor and behavioral deficits. Here, we describe a novel caspase-6 inhibitor peptide based on the huntingtin caspase-6 cleavage site, fused with a cell-penetrating sequence. The peptide reduces mutant Huntingtin proteolysis by caspase-6, and protects cells from mutant Huntingtin toxicity. Continuous subcutaneous administration of the peptide protected pre-symptomatic BACHD mice from motor deficits and behavioral abnormalities. Moreover, administration of the peptide in an advanced disease state resulted in the partial recovery of motor performance, and an alleviation of depression-related behavior and cognitive deficits. Our findings reveal the potential of substrate-based caspase inhibition as a therapeutic strategy, and present a promising agent for the treatment of HD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Caspase 6 / metabolism*
  • Caspase Inhibitors / administration & dosage
  • Caspase Inhibitors / pharmacology*
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Female
  • Huntingtin Protein
  • Huntington Disease / drug therapy
  • Huntington Disease / genetics
  • Huntington Disease / physiopathology
  • Male
  • Mice
  • Mutation*
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics*
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics*
  • Peptides / administration & dosage
  • Peptides / pharmacology*
  • Psychomotor Performance / drug effects*


  • Caspase Inhibitors
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Nuclear Proteins
  • Peptides
  • Caspase 6