The goal of the proposed studies is to advance our understanding of how environmental agents (i.e. metals and pesticides) might interact with constitutive proteins (i.e. alpha-synuclein) and how such interactions could lead to protein aggregation and neuronal degeneration in Parkinson's Disease. Preliminary results obtained in the investigator's laboratory indicate that self-aggregation of alpha-synuclein is dramatically enhanced in the presence of either aluminum or the fungicide diethyldithiocarbamate (DDC). The underlying molecular basis of these interactions will be evaluated in vitro in order to test the hypothesis that increased alpha-synuclein aggregation is a consequence of changes in its conformation, association properties and the structure of its fibrils caused by aluminum or DDC. The possibility that other metals and pesticides (or combinations of agents) are capable of affecting the rate of alpha-synuclein aggregation will also be tested experimentally. The consequences of interactions between alpha-synuclein and metals and pesticides will then be evaluated in an in vivo animal model, i.e. transgenic mice overexpressing human alpha-synuclein under the tyrosine hydroxylase promoter. Because these mice express high levels of alpha- synuclein protein within dopaminergic neurons, they provide a valuable model in which to assess the pathologic consequences of interactions of alpha- synuclein with environmental agents. The first hypothesis to be tested in these animals is that exposure to aluminum or DDC (or other metals and pesticides) induces the aggregation of alpha-synuclein and formation of Lewy body-like inclusions (Lewy bodies are one of the pathologic hallmark of Parkinson's Disease). The second hypothesis is that an impairment of proteasome activity (a key pathway of cellular protein degradation) plays a role in metal- and pesticide-induced Lewy body-like formation. To address this hypothesis, the occurrence of alpha-synuclein-containing inclusions will be monitored in overexpressing mice exposed to metals and pesticides in the presence of inhibitors of the proteasome activity. The final hypothesis is that overexpression of alpha-synuclein increases the vulnerability of the nigrostriatal system to injury caused by metals and pesticides. Mice will be exposed to aluminum or DDC (or other metals and pesticides) and dopaminergic cell damage will be compared in overexpressing versus non-overexpressing animal. Results of these experiments are likely to clarify the mechanisms of alpha-synuclein aggregation and its role in Lewy body formation. Perhaps most importantly, however, they will further our understanding of the relationship between inclusion bodies, dopaminergic degeneration and metals and pesticides, both of which have been implicated in the etiology of idiopathic Parkinson's Disease.
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