title: A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation.
abstract: Recent studies have demonstrated that activated microglia play an important role in dopamine (DA) neuronal degeneration in Parkinson disease (PD) by generating NADPH-oxidase (NADPHO)-derived superoxide. However, the molecular mechanisms that underlie microglial activation in DA cell death are still disputed. We report here that matrix metalloproteinase-3 (MMP-3) was newly induced and activated in stressed DA cells, and the active form of MMP-3 (actMMP-3) was released into the medium. The released actMMP-3, as well as catalytically active recombinant MMP-3 (cMMP-3) led to microglial activation and superoxide generation in microglia and enhanced DA cell death. cMMP-3 caused DA cell death in mesencephalic neuron-glia mixed culture of wild-type (WT) mice, but this was attenuated in the culture of NADPHO subunit null mice (gp91(phox-/-)), suggesting that NADPHO mediated the cMMP-3-induced microglial production of superoxide and DA cell death. Furthermore, in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected animal model of PD, nigrostriatal DA neuronal degeneration, microglial activation, and superoxide generation were largely attenuated in MMP-3-/- mice. These results indicate that actMMP-3 released from stressed DA neurons is responsible for microglial activation and generation of NADPHO-derived superoxide and eventually enhances nigrostriatal DA neuronal degeneration. Our results could lead to a novel therapeutic approach to PD.
authors.affiliation: Burke Medical Research Institute, and Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021, USA.
authors.forename: Yoon Seong
authors.initials: YS
authors.lastname: Kim
authors.forename: Dong Hee
authors.initials: DH
authors.lastname: Choi
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Block
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorenzl
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Youn Jung
authors.initials: YJ
authors.lastname: Kim
authors.forename: Shuei
authors.initials: S
authors.lastname: Sugama
authors.forename: Byung Pil
authors.initials: BP
authors.lastname: Cho
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
authors.forename: Susan E
authors.initials: SE
authors.lastname: Browne
authors.forename: Soo Yul
authors.initials: SY
authors.lastname: Kim
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Tong H
authors.initials: TH
authors.lastname: Joh
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: D008562:Membrane Glycoproteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019278:Matrix Metalloproteinase 3; D004298:Dopamine