title: Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease.
abstract: 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 protease families-caspases and calpains. Identifying critical proteases 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. We screened 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 Hdh(111Q/111Q) cells. Correspondingly, MMPs are activated in HD mouse models, and loss of function of Drosophila homologs of MMPs suppresses Htt-induced neuronal dysfunction in vivo.
authors.affiliation: Buck Institute for Age Research, Novato, CA 94945, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Miller
authors.forename: Jennifer
authors.initials: J
authors.lastname: Holcomb
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.forename: Maria
authors.initials: M
authors.lastname: de Haro
authors.forename: Juliette
authors.initials: J
authors.lastname: Gafni
authors.forename: Ningzhe
authors.initials: N
authors.lastname: Zhang
authors.forename: Eugene
authors.initials: E
authors.lastname: Kim
authors.forename: Mario
authors.initials: M
authors.lastname: Sanhueza
authors.forename: Cameron
authors.initials: C
authors.lastname: Torcassi
authors.forename: Seung
authors.initials: S
authors.lastname: Kwak
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hughes
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004330:Drosophila; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D020782:Matrix Metalloproteinases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D014162:Transfection / Q000379:methods
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D034741:RNA, Small Interfering; C097188:polyglutamine; D020169:Caspases; D020782:Matrix Metalloproteinases