? ? The rationale for the proposed studies is two fold. First, they are designed to address important scientific questions concerning the role of neurotoxicants in the pathogenesis of synucleinopathies, including Parkinson's disease (PD). Second, they will be a vehicle for developing collaborative efforts between the CCPDER Centers at the Parkinson 's Institute and Emory University. The general hypothesis underlying this research is that changes in brain levels and conformation of the protein alpha-synuclein are triggered by exposure to environmental agents and that these alpha-synuclein-toxicant interactions contribute to the pathogenesis of sporadic PD. Based on the investigators' preliminary results showing a robust up-regulation of alpha-synuclein in the substantia nigra of monkeys treated with the neurotoxicant MPTP, four specific aims have been designed to elucidate the relationship between toxicant exposure, tissue injury, enhanced alpha-synuclein levels and formation of intraneuronal inclusions in non-human primates. The first and second specific aims will test the hypotheses that levels of alpha-synuclein remain persistently elevated after repeated toxic exposures and that a sustained upregulation of alpha-synuclein is a common consequence of toxic insults in the primate brain. To test these hypotheses the investigators' collaborative work will involve experiments with MPTP as well as two neurotoxic pesticides, paraquat and rotenone. Findings of these experiments will likely have important implications for our understanding of how environmental exposures could play a role in PD etiology. A critical step toward unraveling the basis of toxicant-induced alpha-synuclein up-regulation is to determine its relation to injury. Therefore, the third specific aim will determine whether a temporal, anatomical and quantitative relationship exists between changes in alpha-synuclein levels and neurodegeneration caused by MPTP, paraquat or rotenone. The last specific aim will begin assessing the pathological consequences of toxicant-induced alpha-synuclein upregulation and will test the hypothesis that a sustained up-regulation of alpha-synuclein may ultimately lead to its pathological aggregation and the formation of Lewy body-like inclusions. The observation of aggregates in one or more of the investigators' paradigms of toxicant-alpha-synuclein interactions would be a result of far-reaching relevance, linking environmental exposures to the pathogenesis of alpha-synuclein-containing inclusions, a key feature of PD and other neurodegenerative diseases. ? ? ?
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