PMID- 17116747
OWN - NLM
STAT- MEDLINE
DCOM- 20070205
LR  - 20220309
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 21
IP  - 1
DP  - 2007 Jan
TI  - A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal 
      degeneration via microglial activation.
PG  - 179-87
AB  - 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.
FAU - Kim, Yoon Seong
AU  - Kim YS
AD  - Burke Medical Research Institute, and Department of Neurology and Neuroscience, 
      Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021, 
      USA.
FAU - Choi, Dong Hee
AU  - Choi DH
FAU - Block, Michelle L
AU  - Block ML
FAU - Lorenzl, Stefan
AU  - Lorenzl S
FAU - Yang, Lichuan
AU  - Yang L
FAU - Kim, Youn Jung
AU  - Kim YJ
FAU - Sugama, Shuei
AU  - Sugama S
FAU - Cho, Byung Pil
AU  - Cho BP
FAU - Hwang, Onyou
AU  - Hwang O
FAU - Browne, Susan E
AU  - Browne SE
FAU - Kim, Soo Yul
AU  - Kim SY
FAU - Hong, Jau-Shyong
AU  - Hong JS
FAU - Beal, M Flint
AU  - Beal MF
FAU - Joh, Tong H
AU  - Joh TH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20061120
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Membrane Glycoproteins)
RN  - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
RN  - EC 1.6.3.- (Cybb protein, mouse)
RN  - EC 1.6.3.- (NADPH Oxidase 2)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/administration & dosage
MH  - Animals
MH  - Cell Death
MH  - Cells, Cultured
MH  - Dopamine/*metabolism
MH  - Matrix Metalloproteinase 3/*metabolism
MH  - Membrane Glycoproteins/genetics/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microglia/*metabolism
MH  - NADPH Oxidase 2
MH  - NADPH Oxidases/genetics/metabolism/physiology
MH  - Neurons/*metabolism/pathology
MH  - Parkinson Disease/enzymology/metabolism/pathology
EDAT- 2006/11/23 09:00
MHDA- 2007/02/06 09:00
CRDT- 2006/11/23 09:00
PHST- 2006/11/23 09:00 [pubmed]
PHST- 2007/02/06 09:00 [medline]
PHST- 2006/11/23 09:00 [entrez]
AID - fj.06-5865com [pii]
AID - 10.1096/fj.06-5865com [doi]
PST - ppublish
SO  - FASEB J. 2007 Jan;21(1):179-87. doi: 10.1096/fj.06-5865com. Epub 2006 Nov 20.