TOXICITY OF CATECHOL THIOETHER ADDUCTS

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Idiopathic Parkinson's disease (PD) is a debilitating, progressive, neurodegenerative disease. Epidemiological studies have identified age and exposure to metals and other toxicants as risk factors for PD. Oxidative stress and mitochondrial dysfunction are hypothesized to be the basic causes of neuron death in PD. The objective of this research proposal is to define the role of catechol adduction in the genesis of PD. Catechols can undergo transition metal-catalyzed autoxidation to quinones and then be reduced to catechols again in a process termed redox cycling. The redox cycling of catechols to quinones leads to the generation of cytotoxic reactive oxygen species and to the formation of catechol thioether adducts via the addition of a thiol to the quinone. A catechol thioether adduct has a lower oxidation potential and may redox cycle at a faster rate than the parent catechol. The first two specific aims of this research are designed to test whether catechol thioether adducts can generate more reactive oxygen species and adduct proteins at a greater rate than native catechols. This will be accomplished by measuring the oxidation potentials of catechol thioether adducts, the reactive oxygen species generated by these adducts, and the rate of protein adduction by these adducts. The last specific aim of this proposal is to test the effects of catechol adduction upon mitochondrial function. This will be accomplished by studying the effects of catechol adducts upon mitochondrial respiration, specific respiratory complexes, and mitochondrial electron carriers.