Search for novel PD biomarkers originating from increased molecular damage and/or deficient molecular quality control systems in the context of PD
Since its discovery in 1997, the DJ-1 enzyme has become one of the most studied proteins in the context of Parkinson’s disease. Although it was originally identified as an oncogene, upregulated in several types of cancer, it is now also recognized as a causative factor in Parkinson’s Disease (PD). Different roles have been associated with DJ-1, including acting as a novel glyoxalase, to detoxify methylglyoxal in a glutathione-independent way and as a deglycase enzyme, to repair the spontaneous glycation of proteins and nucleotides, thereby preventing their inactivation.
Starting from these important shreds of evidence, we would like to further investigate the role of DJ-1 in the detoxification of dicarbonyl species (such as methylglyoxal and glyoxal). These molecules are of particular interest due to their putative role as biomarkers for early disease detection. Our first objective is to use yeast models to characterize at the metabolomic level the pathways affected by DJ-1 knockout and functional mutants using the cutting-edge “Peak Annotation and Verification Engine (PAVE) for microbial untargeted metabolomics data annotation”. This is possible because DJ-1 is a conserved protein and the yeast genome encodes a homolog of human DJ-1 (Hsp31). In comparison to the other omics, metabolomics is closer to the phenotype, and it can sometimes better detect subtle changes in cells with certain genetic deficiencies. Metabolic findings in yeast will in a second step be validated in human neuronal cell lines deficient in DJ-1. Furthermore, we aim to perform in vitro studies using purified recombinant DJ-1 to clarify the primary enzymatic function of this protein and answer our main question: does this enzyme act as a glyoxalase or a deglycase? This project is designed to generate important insights towards the discovery of novel biomarker candidates for PD and to further elucidate the molecular mechanisms involved in this disease.