Journal
NEUROSCIENCE RESEARCH
Volume 67, Issue 3, Pages 203-208Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neures.2010.04.002
Keywords
DJ-1; ASK1; Thioredoxin 1; Oxidative stress; Parkinson's disease (PD)
Categories
Funding
- National Institutes of Health [NS053517, NS059869]
- American Parkinson Disease Association
- Foundation of UMDNJ
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DJ-1 is a multifunctional protein linked to recessively inherited Parkinson's disease (PD) due to loss of function mutations. Among its activities is anti-oxidant property leading to cytoprotection under oxidative stress conditions. A key effector of oxidant-induced cell death is the MAP3 kinase apoptosis signal-regulating kinase 1 (ASK1) which is bound to and inhibited by thioredoxin 1 (Trx1) under basal conditions. Upon oxidative stimuli, however, ASK1 dissociates from this physiological inhibitor and is activated. In the present study, we investigated the role of DJ-1 in regulating Trx1/ASK1 interaction. Over-expression of DJ-1 suppressed ASK1 activation in response to H2O2 in a time-dependent manner. Wild-type DJ-1, but not the PD-associated L166P mutant, prevented the dissociation of ASK1 from Trx1 in response to H2O2. Among cysteine mutants of DJ-1, C46S, C53S, and C106S. only C106S failed to inhibit this dissociation implying that cysteine 106 is essential for Trx1/ASK1 regulation. Furthermore, compared to wild-type mice, DJ-1 null mouse brain homogenates and embryonic fibroblasts were more susceptible to oxidant-induced dissociation of ASK1 from Trx1,activation of the downstream kinase c-Jun N-terminal kinase, and to cell death. These findings point to yet another mechanism through which DJ-1 has anti-oxidant and cytoprotective properties by regulating the Trx1/ASK1 complex and controlling the availability of ASK1 to effect apoptosis. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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