The Parkinsonism/dementia complex of Guam (PDC) bears significant clinical similarities to conventional Parkinson's Disease, and to conventional Alzheimer's disease. As is the case with the conventional disorders, the cause of PDC is unknown. The unusual geographical clustering of PDC and the inability to analyze PDC in terms of conventional patterns of inheritance have lead to the hypothesis that PDC is the result of an environmental toxin (e.g. cycasin) although a pathogenic link has not been proven. This laboratory and other laboratories have demonstrated specific abnormalities of the mitochondrial electron transport chain in both Parkinson's disease and Alzheimer's disease. A significant body of evidence suggests these defects have pathogenic significance. We have demonstrated that PDC patients have similar mitochondrial defects which may be pathogenic. This project will pursue the hypothesis that PDC is characterized by specific mitochondrial defects and that the mitochondrial genome is important in producing these defects. Previous data dealing with PDC will be expanded to include studies of the mitochondrial electron transport chain in Guam motor-neuron disease patients. The occurrence of these specific biochemical defects will be investigated in autopsy samples from brain, myocardium, and skeletal muscle. In order to evaluate the hypothesized role of the mitochondrial genome in the production of these biochemical lesions, mitochondrial DNA will be transfered from patient and control platelets into recently prepared mitochondrial DNA deficient host cell lines and the resulting biochemical phenotype will be assayed. Positive results will indicate involvement of the Mitochondrial genome in PDC. These experiments will be done with platelets from Guam patients and controls and with equivalent samples from the San Diego Chamorro cohort. Finally, we will evaluate the effects of various putative pathogenic toxins on mitochondrial electron transport chain activities rat brain with the goal of determining whether or not any of these toxins can produce the biochemical defects observed in these patients. This project will extend early and very important observations about potential pathogenic mechanisms in PDC/motorneuron disease, provide data on previously unexplored biochemical actions of potential pathogenic toxins, and evaluate a novel hypothesis regarding cause of this disorder. This project will also reinforce the observed biochemical and genetic.
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