Parkinson's disease (PD) is a chronic neurodegenerative disorder that affects millions of people worldwide. The etiology of PD remains largely unexplained. There is, however, increasing experimental and epidemiologic evidence that environmental toxicants are etiologically related to the development of PD. Recent thinking on PD causation also emphasizes the significance of gene/environment interactions, whereby persons who carry genotypes predictive of either a diminished capacity for chemical detoxification or enhanced propensity to activate proneurotoxicants are most susceptible to environmentally-induced PD. The investigators are proposing to extend their ongoing population-based case-control study which is investigating the effects of environmental and genotypic risk factors, and their interactions, on risk of PD. The target goal for the study will be 400 newly diagnosed idiopathic PD cases and 600 age/gender/race-matched controls free of PD and other major neurodegenerative disorders. Study subjects are identified from a defined population source, Group Health Cooperative of Puget Sound, Washington. Exposures of greatest a priority interest are industrial solvents, heavy metals, and pesticides. The investigators will also investigate the unique and interactive associations of known polymorphisms of genes encoding enzymes pertinent to environmental chemical activation and/or detoxification, including: type B monoamine oxidase (MAO-B), cytochromes P450 (CYP) 2D6 and 2EI, and the MI, TI, and PI isozymes of glutathiorie S-transferase (GST). A unifying hypothesis of PD pathogenesis underlying this research is that chemicals that provoke oxidative stress reactions destroy dopaminergic neurons preferentially among persons with genetically determined susceptibilities. Novel features of this project will be the investigators efforts to identify previously unknown genetic polymorphisms of MAO-B and GSTM. In addition, they will conduct a series of in vitro experiments to determine the functional significance of several MAO-B and GST polymorphisms to characterize further mechanistic relation, with PD pathogenesis. Insofar as the causation of PD remains elusive, this investigation will generate important new scientific and public health knowledge. Furthermore, this project may ultimately serve as a model approach for investigating the complex interplay between environmental exposures and host factors on risk for neurodegenerative disorders.
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