DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death.
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.
Neurology/Neuroscience Department, Weill Medical College of Cornell University, New York, New York, USA.
Dong-Hee
DH
Choi
Onyou
O
Hwang
Kyoung-Hee
KH
Lee
Jongmin
J
Lee
M Flint
MF
Beal
Yoon-Seong
YS
Kim
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D057075:Enzyme Assays; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D015513:Oncogene Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D019278:Matrix Metalloproteinase 3; D009498:Neurotoxins; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014446:Tyrosine 3-Monooxygenase; D000099156:Superoxide Dismutase 2; C105131:PARK7 protein, human; C511769:Mmp3 protein, mouse