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

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

Research output: Contribution to journalArticle

139 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)179-187
Number of pages9
JournalFASEB Journal
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Keywords

  • Dopamine neuron protection

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Yoon, S. K., Dong, H. C., Block, M. L., Lorenzl, S., Yang, L., Youn, J. K., Sugama, S., Byung, P. C., Hwang, O., Browne, S. E., Soo, Y. K., Hong, J. S., Beal, M. F., & Joh, T. H. (2007). A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. FASEB Journal, 21(1), 179-187. https://doi.org/10.1096/fj.06-5865com