Matrix Metalloproteinases Are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington's Disease
2010; Cell Press; Volume: 67; Issue: 2 Linguagem: Inglês
10.1016/j.neuron.2010.06.021
ISSN1097-4199
AutoresJohn P. Miller, Jennifer Holcomb, Ismael Al‐Ramahi, María de Haro, Juliette Gafni, Ningzhe Zhang, Eugene S. Kim, Mario Sanhueza, Cameron Torcassi, Seung Kwak, Juan Botas, Robert E. Hughes, Lisa Ellerby,
Tópico(s)Mitochondrial Function and Pathology
ResumoProteolytic 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 Hdh111Q/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.PaperClip/cms/asset/f2e383e1-7a8a-4257-b0fa-f6592f067b85/mmc2.mp3Loading ...(mp3, 3.06 MB) Download audio
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