The etiology of Parkinson's disease (PD) is largely unknown, although there is growing evidence that environmental agents play an important role. The discovery of MPTP as an exogenous cause of Parkinsonism in humans, and subsequent experimental confirmation, continue to provide models for PD induction. Increasingly, epidemiologic studies have identified agents that induce oxidative stress, including various pesticides and metals, as candidate risk factors. Genetic predisposition to PD conferred by defective metabolism of oxidative stressors has been postulated as a potentially significant component of some causal pathways. During the past 3 years, we have conducted a community-based-control study that is testing the hypotheses that environmental oxidative stressors are PD risk factors, with effects modified by underlying host susceptibility traits. We are currently proposing to extend the ongoing case-control study by enlarging the study size and adding biochemical and genetic markers of potential risk susceptibility. The underlying ecogenetic hypotheses remain as: 1) certain oxidative stressor environmental agents, acting in concert with normal nervous system aging processes, increase PD risk; and 2) metabolic deficiencies are effect modifiers of these exposures. New aspects of the study will be a more in-depth molecular biology approach to characterize host susceptibility profiles and an increased focus on the previously seen inverse relation of PD risk with cigarette smoking. The target study size will be increased from 100 PD cases and 100 controls to 300 cases and 300 controls. As before, data on demographic variables, residential history, smoking, and occupational and environmental exposures will be obtained from structured questionnaires. Biomarkers of susceptibility, assayed from peripheral blood cells, include monoamine oxidase B (MAO-B) activity in platelets, MAO-B gene polymorphism, cytosolic and mitochondrial superoxide dismutase activity (SOD) in lymphocytes, protein and mRNA levels of the two forms of SOD in lymphocytes, and genotype of the cytochrome P450, debrisoquine hydroxylase (CYP2D60. The newly proposed biomarkers, MAO-B allele genotype and SOD mRNA and protein levels, should permit more in- depth examinations of underlying genetic determinants of expression of these enzyme systems than mere activity measurement. This study will ultimately be one of the world's largest and most comprehensive assessments of the ocogenetics of PD. Information derived from this research should therefore and greatly to the understanding of the interactive roles of exposures to enviornmental agents, normal aging processes, and host susceptibilities in PD induction.
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