Aharony Israel, Ehrnhoefer Dagmar E, Shruster Adi, Qiu Xiaofan, Franciosi Sonia, Hayden Michael R, Offen Daniel
Neuroscience Laboratory, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel and.
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
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.
在过去十年中，越来越多的证据表明半胱天冬酶-6活性与亨廷顿舞蹈症（HD）的发病机制之间存在重要联系。因此，抑制半胱天冬酶-6活性被认为是一种有前景的治疗策略，可降低突变型亨廷顿蛋白的毒性，并防止其诱导的运动和行为缺陷。在此，我们描述了一种基于亨廷顿蛋白半胱天冬酶-6切割位点的新型半胱天冬酶-6抑制剂肽，其与细胞穿透序列融合。该肽可减少半胱天冬酶-6对突变型亨廷顿蛋白的蛋白水解作用，并保护细胞免受突变型亨廷顿蛋白的毒性影响。连续皮下注射该肽可保护症状前的BACHD小鼠免受运动缺陷和行为异常的影响。此外，在疾病晚期给药该肽可导致运动能力部分恢复，并减轻与抑郁相关的行为和认知缺陷。我们的研究结果揭示了基于底物的半胱天冬酶抑制作为一种治疗策略的潜力，并为HD的治疗提供了一种有前景的药物。
