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A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation

Yoon Seong Kim^*,,1, Dong Hee Choi^*,,1, Michelle L. Block^,1, Stefan Lorenzl, Lichuan Yang, Youn Jung Kim^*, Shuei Sugama^*,, Byung Pil Cho^*, Onyou Hwang, Susan E. Browne, Soo Yul Kim^*,, Jau-Shyong Hong, M. Flint Beal and Tong H. Joh^,||,2

^* Burke Medical Research Institute,

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, New York;

Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea;

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; and

^|| Kyung Hee University, College of Oriental Medicine, Seoul, South Korea

²Correspondence: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Rm. F610, 1300 York Ave., New York, NY 10021. E-mail: thjoh{at}med.cornell.edu

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, 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.

Key Words: dopamine neuron protection