A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation.
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.
Kim
Yoon Seong
YS
Burke Medical Research Institute, and Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021, USA.
Choi
Dong Hee
DH
Block
Michelle L
ML
Lorenzl
Stefan
S
Yang
Lichuan
L
Kim
Youn Jung
YJ
Sugama
Shuei
S
Cho
Byung Pil
BP
Hwang
Onyou
O
Browne
Susan E
SE
Kim
Soo Yul
SY
Hong
Jau-Shyong
JS
Beal
M Flint
MF
Joh
Tong H
TH
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
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