Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease.
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.
Miller
John P
JP
Buck Institute for Age Research, Novato, CA 94945, USA.
Holcomb
Jennifer
J
Al-Ramahi
Ismael
I
de Haro
Maria
M
Gafni
Juliette
J
Zhang
Ningzhe
N
Kim
Eugene
E
Sanhueza
Mario
M
Torcassi
Cameron
C
Kwak
Seung
S
Botas
Juan
J
Hughes
Robert E
RE
Ellerby
Lisa M
LM
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
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