title: Matrix metalloproteinase-3 causes dopaminergic neuronal death through Nox1-regenerated oxidative stress.
abstract: In the present study we investigated the interplay between matrix metalloproteinase 3 (MMP3) and NADPH oxidase 1 (Nox1) in the process of dopamine (DA) neuronal death. We found that MMP3 activation causes the induction of Nox1 via mitochondrial reactive oxygen species (ROS) production and subsequently Rac1 activation, eventually leading to Nox1-derived superoxide generation in a rat DA neuronal N27 cells exposed to 6-OHDA. While a MMP3 inhibitor, NNGH, largely attenuated mitochondrial ROS and subsequent Nox1 induction, both apocynin, a putative Nox inhibitor and GKT137831, a Nox1 selective inhibitor failed to reduce 6-OHDA-induced mitochondrial ROS. However, both inhibitors for MMP3 and Nox1 similarly attenuated 6-OHDA-induced N27 cell death. RNAi-mediated selective inhibition of MMP3 or Nox1 showed that knockdown of either MMP3 or Nox1 significantly reduced 6-OHDA-induced ROS generation in N27 cells. While 6-OHDA-induced Nox1 was abolished by MMP3 knockdown, Nox1 knockdown did not alter MMP3 expression. Direct overexpression of autoactivated MMP3 (actMMP3) in N27 cells or in rat substantia nigra (SN) increased expression of Nox1. Selective knockdown of Nox1 in the SN achieved by adeno-associated virus-mediated overexpression of Nox1-specific shRNA largely attenuated the actMMP3-mediated dopaminergic neuronal loss. Furthermore, Nox1 expression was significantly attenuated in Mmp3 null mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Together we established novel molecular mechanisms underlying oxidative stress-mediated dopaminergic neuronal death in which MMP3 activation is a key upstream event that leads to mitochondrial ROS, Nox1 induction and eventual dopaminergic neuronal death. Our findings may lead to the development of novel therapeutic approach.
authors.affiliation: Center for Neuroscience Research, Institute of Biomedical Science and technology, Konkuk University, Seoul, 143-701, Korea; Department of Medical Science, Konkuk University School of Medicine, Seoul, 143-701, Korea.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Center for Neuroscience Research, Institute of Biomedical Science and technology, Konkuk University, Seoul, 143-701, Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Center for Neuroscience Research, Institute of Biomedical Science and technology, Konkuk University, Seoul, 143-701, Korea.
authors.forename: Joo-Ha
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Center for Neuroscience Research, Institute of Biomedical Science and technology, Konkuk University, Seoul, 143-701, Korea; Department of Rehabilitation Medicine, Konkuk University School of Medicine, Seoul, 143-701, Korea.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Immunology and Physiology, Functional Genomics Institute, College of Medicine, Konkuk University, Chungju, 380-701, Korea.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, 32827, United States of America.
authors.forename: Yoon-Seong
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; C000614712:NOX1 protein, rat; D019278:Matrix Metalloproteinase 3; D004298:Dopamine