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DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex
Joo-Young Im1, Kang-Woo Lee, Eunsung Junn
1Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Neuroscience Research
|April 14, 2010
Summary
DJ-1 protein protects cells from oxidative stress by regulating the thioredoxin 1 (Trx1) and apoptosis signal-regulating kinase 1 (ASK1) interaction. This mechanism is crucial for preventing cell death in Parkinson
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Parkinson's disease (PD) is linked to DJ-1 mutations.
- DJ-1 has antioxidant properties and protects cells from oxidative stress.
- Apoptosis signal-regulating kinase 1 (ASK1) is activated by oxidative stress, leading to cell death.
Purpose of the Study:
- To investigate DJ-1's role in regulating the interaction between thioredoxin 1 (Trx1) and ASK1.
- To determine the specific DJ-1 cysteine residues involved in this regulation.
Main Methods:
- Over-expression of wild-type and mutant DJ-1 in cells.
- Treatment with hydrogen peroxide (H2O2) to induce oxidative stress.
- Analysis of ASK1 dissociation from Trx1, downstream kinase activation, and cell death in wild-type and DJ-1 null mouse tissues and cells.
Main Results:
- Over-expression of DJ-1 suppressed ASK1 activation and prevented ASK1/Trx1 dissociation under oxidative stress.
- Wild-type DJ-1, but not the L166P mutant, inhibited ASK1/Trx1 dissociation.
- DJ-1 cysteine 106 (C106) is essential for regulating the ASK1/Trx1 interaction.
- DJ-1 null cells and tissues showed increased susceptibility to oxidant-induced cell death.
Conclusions:
- DJ-1 regulates the Trx1/ASK1 complex, preventing ASK1 activation and subsequent cell death.
- Cysteine 106 of DJ-1 is critical for its cytoprotective function.
- DJ-1's regulation of the Trx1/ASK1 pathway is a key antioxidant mechanism relevant to Parkinson's disease.
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