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bioRxiv · 10.1101/2022.02.18.481064

DJ-1 glyoxalase activity makes a modest contribution to cellular defense against methylglyoxal damage in neurons

Mazza, M. C.·Shuck, S.·Lin, J.·Moxley, M. A.·Termini, J.·Cookson, M. R.·Wilson, M. A.
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Abstract

Human DJ-1 is a cytoprotective protein whose absence causes Parkinsons disease and is also associated with other diseases. DJ-1 has an established role as a redox-regulated protein that defends against oxidative stress and mitochondrial dysfunction. Multiple studies have suggested that DJ-1 is also a protein/nucleic acid deglycase that plays a key role in the repair of glycation damage caused by methylglyoxal (MG), a reactive -keto aldehyde formed by central metabolism. Contradictory reports suggest that DJ-1 is a glyoxalase but not a deglycase and does not play a major role in glycation defense. Resolving this issue is important for understanding how DJ-1 protects cells against insults that can cause disease. We find that DJ-1 reduces levels of reversible adducts of MG with guanine and cysteine in vitro. The steady-state kinetics of DJ-1 acting on reversible hemithioacetal substrates are fitted adequately with a computational kinetic model that requires only a DJ-1 glyoxalase activity, supporting the conclusion that deglycation is an apparent rather than a true activity of DJ-1. Sensitive and quantitative isotope-dilution mass spectrometry shows that DJ-1 modestly reduces the levels of some irreversible guanine and lysine glycation products in primary and cultured neuronal cell lines and whole mouse brain, consistent with a small but measurable effect on total neuronal glycation burden. However, DJ-1 does not improve cultured cell viability in exogenous MG. In total, our results suggest that DJ-1 is not a deglycase and has only a minor role in protecting neurons against methylglyoxal toxicity.

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Mazza, M. C., Shuck, S., Lin, J., Moxley, M. A., Termini, J., Cookson, M. R., Wilson, M. A.. 2022-02-18. DJ-1 glyoxalase activity makes a modest contribution to cellular defense against methylglyoxal damage in neurons. https://doi.org/10.1101/2022.02.18.481064

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