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A pivotal role of matrix metalloproteinase‐3 activity in dopaminergic neuronal degeneration via microglial activation
Author(s) -
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 JauShyong,
Flint Beal M.,
Joh Tong H.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-5865com
Subject(s) - microglia , superoxide , mptp , programmed cell death , nadph oxidase , chemistry , microbiology and biotechnology , dopaminergic , substantia nigra , neuroscience , dopamine , biology , reactive oxygen species , biochemistry , immunology , apoptosis , inflammation , enzyme
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 (c MMP‐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 ( gp 91 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, 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. FASEB J. 21, 179–187 (2007)