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

Abstract

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.

• Authors: Israel Aharony, Dagmar E Ehrnhoefer, Adi Shruster, Xiaofan Qiu, Sonia Franciosi, Michael R Hayden, Daniel Offen
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 9 Pg. 2604-14 (May 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25616965 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

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

Topics

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