Document Detail


DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death.
MedLine Citation:
PMID:  20969476     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Oxidative stress is commonly implicated in aging and neurodegenerative conditions such as Parkinson's disease (PD). Mutations in DJ-1 are associated with autosomal recessive early-onset PD. We investigated whether DJ-1 can be degraded in oxidative-stressed dopaminergic neuronal cells, leading to loss of its protective role against oxidative stress. We have shown previously and herein that the active form of matrix metalloproteinase-3 (MMP3) was accumulated in dopamine-producing CATH.a cells in the presence of MPP(+). We show that catalytically active MMP3 cleaved DJ-1, and impaired its antioxidant function. In CATH.a cells, both monomeric and dimeric forms of DJ-1 were diminished in the presence of MPP(+), and this was reversed by MMP3 knockdown or inhibition. While DJ-1 expression was decreased in the substantia nigra of mice administered with MPTP, its degradation was largely attenuated in MMP3 knockout mice. The AKT-signaling pathway, thought to mediate the effect of DJ-1 on cell survival, was also altered. MPP(+) caused decrease in both phospho-Thr308 and phospho-Ser473 forms of AKT, and this was restored by NNGH. Our data suggest that DJ-1 is fragmented by the intracellular MMP3 in response to cell stress, abolishing the protective role of DJ-1 against oxidative damage, and this contributes to the pathogenesis of PD.
Authors:
Dong-Hee Choi; Onyou Hwang; Kyoung-Hee Lee; Jongmin Lee; M Flint Beal; Yoon-Seong Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-10
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  14     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-13     Completed Date:  2011-11-01     Revised Date:  2014-06-18    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2137-50     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
1-Methyl-4-phenylpyridinium / pharmacology
Animals
Antioxidants / metabolism*
Cell Death
Cell Line
Enzyme Assays
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Matrix Metalloproteinase 3 / genetics*,  metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons / drug effects,  physiology*
Neurotoxins / pharmacology
Oncogene Proteins / metabolism*
Oxidative Stress / drug effects*
Reactive Oxygen Species / metabolism
Substantia Nigra / drug effects,  metabolism
Superoxide Dismutase / metabolism
Tyrosine 3-Monooxygenase / metabolism
Grant Support
ID/Acronym/Agency:
R01 NS062827/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Intracellular Signaling Peptides and Proteins; 0/Neurotoxins; 0/Oncogene Proteins; 0/PARK7 protein, human; 0/Reactive Oxygen Species; 9P21XSP91P/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; EC 1.14.16.2/Tyrosine 3-Monooxygenase; EC 1.15.1.1/Superoxide Dismutase; EC 1.15.1.1/superoxide dismutase 2; EC 3.4.24.17/Matrix Metalloproteinase 3; EC 3.4.24.17/Mmp3 protein, mouse; R865A5OY8J/1-Methyl-4-phenylpyridinium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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