| First Author | Im JY | Year | 2010 |
| Journal | Neurosci Res | Volume | 67 |
| Issue | 3 | Pages | 203-8 |
| PubMed ID | 20385180 | Mgi Jnum | J:161867 |
| Mgi Id | MGI:4461834 | Doi | 10.1016/j.neures.2010.04.002 |
| Citation | Im JY, et al. (2010) DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex. Neurosci Res 67(3):203-8 |
| abstractText | 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 H(2)O(2) 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 H(2)O(2). 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. |
