DJ‐1 is not a deglycase and makes a modest contribution to cellular defense against methylglyoxal damage in neurons

Abstract

Human DJ-1 is a cytoprotective protein whose absence causes Parkinson's disease and is also associated with other diseases. DJ-1 has an established role as a redoxregulated 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 α-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.

DJ-1 and SOD1 Act Independently in the Protection against Anoxia in Drosophila melanogaster

“…In other words, the strong phenotypes caused by the loss of Ccs could be too strong to allow the detection of the limited protective effects mediated by dj-1β. In agreement with this hypothesis, it has recently been shown that while the loss of DJ-1 makes cells more sensitive to methylglyoxal-associated glycation, its overexpression does not improve cellular viability against the toxicity of exogenously added methylglyoxal [ 37 ].…”

Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model

“…Early work proposed that DJ1 integrates with the glycation stress system through enzymatic function (Hasim et al, 2014), participates in MGO degradation, or prevents permanent glycation damage by direct repair of early glycation products (Richarme et al, 2015(Richarme et al, , 2017. In patient derived iPSC neurons bearing DJ1 mutation glycation related products were found elevated (Mazza et al, 2022). However, DJ1 deficiency fail to enhance neuronal cell death when challenged with MGO (Mazza et al, 2022).…”

“…In patient derived iPSC neurons bearing DJ1 mutation glycation related products were found elevated (Mazza et al, 2022). However, DJ1 deficiency fail to enhance neuronal cell death when challenged with MGO (Mazza et al, 2022). In the DJ1 KO organoids, we observe a progressive accumulation of glycated proteins starting at day 100.…”

Saccharomyces cerevisiae DJ-1 paralogs maintain genome integrity through glycation repair of nucleic acids and proteins

“…This enables cells to efficiently reutilize the cellular proteome pool ( Figure 8 ). In contrast, human DJ-1 exhibited weaker methylglyoxalase and deglycase activity than yeast and plant counterparts (Mazza et al, 2022).…”