title: 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.affiliation: Neuroscience Laboratory, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel and.
authors.forename: Israel
authors.initials: I
authors.lastname: Aharony
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dagmar E
authors.initials: DE
authors.lastname: Ehrnhoefer
authors.affiliation: Neuroscience Laboratory, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel and.
authors.forename: Adi
authors.initials: A
authors.lastname: Shruster
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Franciosi
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Neuroscience Laboratory, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel and danioffen@gmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D053178:Caspase 6 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects*
chemical_list: D061945:Caspase Inhibitors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; D053178:Caspase 6