Superfund Research Program
Role of Paraoxonases (PONs) in Modulating Cadmium and Manganese Neurotoxicity
The studies by Clement Furlong, Ph.D., and his research team on factors that inhibit the activity of the antioxidant protein PON1 that protects HDL and LDL from oxidation demonstrated that products of lipid oxidation resulting from oxidative stress from exposure to cadmium (Cd) or manganese (Mn) significantly inhibit the activity of PON1, in some cases at concentrations of lipid peroxidation products that are not considered pathological. The research team’s earlier results suggested that the related mitochondrial-associated protein PON2 protected PON1 from inhibition most likely through modulating oxidative stress in mitochondria. The generation of recombinant mouse PON2 will allow the researchers to directly examine the protective role of PON2 modulating oxidative stress related to disease. The research team have re-designed and synthesized mouse PON2 cDNA and are currently expressing it in different strains of E. coli. The use of PON2-deficient mice provides a platform for examining the role of PON2 in the dopaminergic system that is important in Parkinson’s disease. There is an upregulation of PON2 mRNA and protein expression in cerebellar granule neurons with a dopamine receptor 2 agonist. The PON2-deficient mice showed impaired motor coordination independently of exposure. This has been confirmed in a new cohort of WT and PON2-deficient littermate mice. The researchers have also found evidence of Mn-derived impairment in memory in PON2-deficient mice, as well as significant increased body weight in Mn-treated male PON2-deficient mice. The data generated to date indicate that high levels of PON2 protect PON1 from the effects of oxidative stress providing an explanation for the lower frequency of cardiovascular disease and Parkinson’s disease in pre-menopausal females.