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...

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Published in:The FASEB journal 2007-01, Vol.21 (1), p.179-187
Main Authors: Kim, Yoon Seong, Choi, Dong Hee, Block, Michelle L, Lorenzl, Stefan, Yang, Lichuan, Kim, Youn Jung, Sugama, Shuei, Cho, Byung Pil, Hwang, Onyou, Browne, Susan E, Kim, Soo Yul, Hong, Jau-Shyong, Beal, M. Flint, Joh, Tong H
Format: Article
Language:English
Subjects:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - administration & dosage
Animals
Cell Death
Cells, Cultured
Dopamine - metabolism
dopamine neuron protection
Matrix Metalloproteinase 3 - metabolism
Membrane Glycoproteins - genetics
Membrane Glycoproteins - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia - metabolism
NADPH Oxidase 2
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
NADPH Oxidases - physiology
Neurons - metabolism
Neurons - pathology
Parkinson Disease - enzymology
Parkinson Disease - metabolism
Parkinson Disease - pathology
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Summary: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 (gp91phox⁻/⁻), 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, Y. S., Choi, D. H., Block, M. L., Lorenzl, S., Yang, L., Kim, Y. J., Sugama, S., Cho, B. P., Ywang, O., Browne, S. E., Kim, S. Y., Hong, J.-S., Beal, M. F., Jon, T. H. A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.06-5865com