PMID- 25536219
OWN - NLM
STAT- MEDLINE
DCOM- 20151201
LR  - 20201217
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 12
DP  - 2014
TI  - Matrix metalloproteinase-3 causes dopaminergic neuronal death through 
      Nox1-regenerated oxidative stress.
PG  - e115954
LID - 10.1371/journal.pone.0115954 [doi]
LID - e115954
AB  - In the present study we investigated the interplay between matrix 
      metalloproteinase 3 (MMP3) and NADPH oxidase 1 (Nox1) in the process of dopamine 
      (DA) neuronal death. We found that MMP3 activation causes the induction of Nox1 
      via mitochondrial reactive oxygen species (ROS) production and subsequently Rac1 
      activation, eventually leading to Nox1-derived superoxide generation in a rat DA 
      neuronal N27 cells exposed to 6-OHDA. While a MMP3 inhibitor, NNGH, largely 
      attenuated mitochondrial ROS and subsequent Nox1 induction, both apocynin, a 
      putative Nox inhibitor and GKT137831, a Nox1 selective inhibitor failed to reduce 
      6-OHDA-induced mitochondrial ROS. However, both inhibitors for MMP3 and Nox1 
      similarly attenuated 6-OHDA-induced N27 cell death. RNAi-mediated selective 
      inhibition of MMP3 or Nox1 showed that knockdown of either MMP3 or Nox1 
      significantly reduced 6-OHDA-induced ROS generation in N27 cells. While 
      6-OHDA-induced Nox1 was abolished by MMP3 knockdown, Nox1 knockdown did not alter 
      MMP3 expression. Direct overexpression of autoactivated MMP3 (actMMP3) in N27 
      cells or in rat substantia nigra (SN) increased expression of Nox1. Selective 
      knockdown of Nox1 in the SN achieved by adeno-associated virus-mediated 
      overexpression of Nox1-specific shRNA largely attenuated the actMMP3-mediated 
      dopaminergic neuronal loss. Furthermore, Nox1 expression was significantly 
      attenuated in Mmp3 null mice treated with 
      N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Together we established 
      novel molecular mechanisms underlying oxidative stress-mediated dopaminergic 
      neuronal death in which MMP3 activation is a key upstream event that leads to 
      mitochondrial ROS, Nox1 induction and eventual dopaminergic neuronal death. Our 
      findings may lead to the development of novel therapeutic approach.
FAU - Choi, Dong-Hee
AU  - Choi DH
AD  - Center for Neuroscience Research, Institute of Biomedical Science and technology, 
      Konkuk University, Seoul, 143-701, Korea; Department of Medical Science, Konkuk 
      University School of Medicine, Seoul, 143-701, Korea.
FAU - Kim, Ji-Hye
AU  - Kim JH
AD  - Center for Neuroscience Research, Institute of Biomedical Science and technology, 
      Konkuk University, Seoul, 143-701, Korea.
FAU - Seo, Joo-Ha
AU  - Seo JH
AD  - Center for Neuroscience Research, Institute of Biomedical Science and technology, 
      Konkuk University, Seoul, 143-701, Korea.
FAU - Lee, Jongmin
AU  - Lee J
AD  - Center for Neuroscience Research, Institute of Biomedical Science and technology, 
      Konkuk University, Seoul, 143-701, Korea; Department of Rehabilitation Medicine, 
      Konkuk University School of Medicine, Seoul, 143-701, Korea.
FAU - Choi, Wahn Soo
AU  - Choi WS
AD  - Department of Immunology and Physiology, Functional Genomics Institute, College 
      of Medicine, Konkuk University, Chungju, 380-701, Korea.
FAU - Kim, Yoon-Seong
AU  - Kim YS
AD  - Burnett School of Biomedical Sciences, College of Medicine, University of Central 
      Florida, Orlando, Florida, 32827, United States of America.
LA  - eng
GR  - R01 NS062827/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141223
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.6.- (NADH, NADPH Oxidoreductases)
RN  - EC 1.6.3.- (NADPH Oxidase 1)
RN  - EC 1.6.3.- (NOX1 protein, mouse)
RN  - EC 1.6.3.- (NOX1 protein, rat)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Cell Death
MH  - Cell Line
MH  - Dopamine/metabolism
MH  - Dopaminergic Neurons/*cytology/*metabolism
MH  - Male
MH  - Matrix Metalloproteinase 3/genetics/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/genetics/metabolism
MH  - NADH, NADPH Oxidoreductases/genetics/*metabolism
MH  - NADPH Oxidase 1
MH  - *Oxidative Stress
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
PMC - PMC4275264
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/12/24 06:00
MHDA- 2015/12/15 06:00
PMCR- 2014/12/23
CRDT- 2014/12/24 06:00
PHST- 2014/08/17 00:00 [received]
PHST- 2014/11/28 00:00 [accepted]
PHST- 2014/12/24 06:00 [entrez]
PHST- 2014/12/24 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2014/12/23 00:00 [pmc-release]
AID - PONE-D-14-36147 [pii]
AID - 10.1371/journal.pone.0115954 [doi]
PST - epublish
SO  - PLoS One. 2014 Dec 23;9(12):e115954. doi: 10.1371/journal.pone.0115954. 
      eCollection 2014.