ABSTRACT
Parkinson's disease is a severe neurodegenerative disease. Several environmental contaminants such as pesticides have been suspected to favor the appearance of this pathology. The protein DJ-1 (or Park7) protects against the development of Parkinson's disease. Thus, the possible inhibitory effects of about a hundred pesticides on human DJ-1 have been studied. We identified fifteen of them as strong inhibitors of DJ-1 with IC50 values between 0.02 and 30 µM. Thiocarbamates are particularly good inhibitors, as shown by thiram that acts as an irreversible inhibitor of an esterase activity of DJ-1 with an IC50 value of 0.02 µM. Thiram was also found as a good inhibitor of the protective activity of DJ-1 against glycation. Such inhibitory effects could be one of the various biological effects of these pesticides that may explain their involvement in the development of Parkinson's disease.
Subject(s)
Neurodegenerative Diseases , Parkinson Disease , Pesticides , Humans , Parkinson Disease/pathology , Pesticides/toxicity , Protein Deglycase DJ-1/genetics , Protein Deglycase DJ-1/metabolism , ThiramABSTRACT
DJ-1 (also called PARK7) is a ubiquitously expressed protein involved in the etiology of Parkinson disease and cancers. At least one of its three cysteine residues is functionally essential, and its oxidation state determines the specific function of the enzyme. DJ-1 was recently reported to be persulfidated in mammalian cell lines, but the implications of this post-translational modification have not yet been analyzed. Here, we report that recombinant DJ-1 is reversibly persulfidated at cysteine 106 by reaction with various sulfane donors and subsequently inhibited. Strikingly, this reaction is orders of magnitude faster than C106 oxidation by H2O2, and persulfidated DJ-1 behaves differently than sulfinylated DJ-1. Both these PTMs most likely play a dedicated role in DJ-1 signaling or protective pathways.
