Parkinson’s disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro

Abstract

DJ-1 (also known as PARK7) has been identified as a causal gene for hereditary recessive Parkinson’s disease (PD). Consequently, the full elucidation of DJ-1 function will help decipher the molecular mechanisms underlying PD pathogenesis. However, because various, and sometimes inconsistent, roles for DJ-1 have been reported, the molecular function of DJ-1 remains controversial. Recently, a number of papers have suggested that DJ-1 family proteins are involved in aldehyde detoxification. We found that DJ-1 indeed converts methylglyoxal (pyruvaldehyde)-adducted glutathione (GSH) to intact GSH and lactate. Based on evidence that DJ-1 functions in mitochondrial homeostasis, we focused on the possibility that DJ-1 protects co-enzyme A (CoA) and its precursor in the CoA synthetic pathway from aldehyde attack. Here, we show that intact CoA and β-alanine, an intermediate in CoA synthesis, are recovered from methylglyoxal-adducts by recombinant DJ-1 purified from E. coli. In this process, methylglyoxal is converted to L-lactate rather than the D-lactate produced by a conventional glyoxalase. PD-related pathogenic mutations of DJ-1 (L10P, M26I, A104T, D149A, and L166P) impair or abolish detoxification activity, suggesting a pathological significance. We infer that a key to understanding the biological function of DJ-1 resides in its methylglyoxal-adduct hydrolase activity, which protects low-molecular thiols, including CoA, from aldehydes.

The apparent deglycase activity of DJ-1 results from the conversion of free methylglyoxal present in fast equilibrium with hemithioacetals and hemiaminals

“…When DJ-1 was added to the mixture, the absorbance at 288 nm gradually decreased ( Fig. 6A), suggesting the degradation of hemithioacetal by DJ-1, consistent with earlier reports (8,18). This effect can be mimicked by Tris buffer (Fig.…”

“…8B). DJ-1-catalyzed conversion of MGO was reported to produce only L-lactate regardless of the presence of thiols (5,18), whereas catalysis by Glx3 produces both D-and L-lactate in comparable amounts (6). This means that more MGO has been converted by Glx3 compared with DJ-1, which is consistent with higher activity of Glx3.…”

“…One possibility is that DJ-1 may detoxify an as yet unidentified neurotoxic molecule structurally similar to MGO. It is also possible that the function of DJ-1 is unrelated to the detoxification of MGO as many of the mutants found in patients with early development of Parkinson's disease have unaltered glyoxalase activity (18). DJ-1 may also serve as a sensor for oxidant stress because its active-site cysteine is prone to oxidation (22,23).…”

The Overcrowded Crossroads: Mitochondria, Alpha-Synuclein, and the Endo-Lysosomal System Interaction in Parkinson’s Disease

“…The gene encodes the 189-amino-acid DJ-1 protein, with studies having demonstrated greater DJ-1 oxidative damage and elevated DJ-1 protein levels in postmortem brains of sporadic PD patients [110]. This ubiquitous pleiotropic protein has been proposed to play a protective role in multiple functions, including redox-sensitive esterase, chaperone for α-syn, protease, transcriptional regulator, the regulator of pro-apoptotic Bax, the regulator of tyrosine hydroxylase in dopamine synthesis, and regulator of the 20S proteasome [111]. DJ-1 has a highly oxidative-stress sensitive cysteine residue at position 106 (Cys-106), which induces DJ-1 localization to the depolarized mitochondria to regulate antioxidant defense and maintain Complex I activity [112,113,114].…”

The Role of DJ-1 in Cellular Metabolism and Pathophysiological Implications for Parkinson’s Disease

“…In addition to its glyoxalase function, Richarme and colleagues proposed that DJ-1 could act as a novel deglycase that repairs methylglyoxal-and glyoxal-glycated amino acids, proteins, nucleotides and nucleic acids by acting on early glycation intermediates and releasing lactate or glycolate [38,39]. Matsuda and colleagues suggested that DJ-1 protects glutathione and coenzyme A (CoA) from aldehyde attack [40]. They found that glutathione (GSH), CoA and β-alanine (a CoA precursor) are recovered from methylglyoxal-adducts by recombinant human DJ-1 purified from E. coli.…”