Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 14, Issue 11, Pages 2137-2150Publisher
MARY ANN LIEBERT INC
DOI: 10.1089/ars.2009.3059
Keywords
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Funding
- Parkinson's Disease Foundation
- Brain Research Center of the Ministry of Education, Science and Technology, the Republic of Korea [2010K000810]
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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. Antioxid. Redox Signal. 14, 2137-2150.
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