Matrix Metalloproteinases Are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington's Disease

Abstract

Summary Proteolytic cleavage of huntingtin (Htt) is known to be a key event in the pathogenesis of Huntington’s disease (HD). Our understanding of proteolytic processing of Htt has thus far focused on the cysteine protease families of caspases and calpains. Identifying critical protease families involved in Htt proteolysis and toxicity using an unbiased approach has not been reported. To accomplish this, we designed a high-throughput western blot-based screen to examine the generation of the smallest N-terminal polyglutamine-containing Htt fragment. Using this approach, we screened a set of 514 siRNAs targeting the repertoire of human protease genes. This screen identified 11 proteases that, when inhibited, reduced Htt fragment accumulation. Three of these belonged to the matrix metalloproteinase (MMP) family. One family member, MMP-10, directly cleaves Htt, and prevents cell death when knocked down in striatal Hdh111Q/111Q cells. Correspondingly, we found MMPs are activated in mouse models of HD, and loss of function of Drosophila homologs of MMPs and four other proteases suppress Htt-induced neuronal dysfunction in vivo.