Parkinson's disease (PD) is a major neurodegenerative disorder affecting approximately 2% of the population over age 50, and the number of annual PD cases continues to rise along with the median age of the population. As the population in our society ages, we face the regrettable reality that effective medical treatment strategies for major chronic neurodegenerative disorders, including Parkinson's disease, are lacking. Determining the mechanisms of etiopathogenesis and selective nigrostriatal degeneration in PD is a formidable challenge. Emerging epidemiological and case control studies suggest that environmental factors, especially pesticides, are dominant risk factors in the etiology of sporadic, geriatric-onset Parkinson's disease. In this proposal, our preliminary data reveal that dopaminergic cells are susceptible to Dieldrin (a potential environmental risk factor for development of PD) -induced apoptosis, in which oxidative stress plays a causal role. We have also uncovered a novel apoptotic pathway involving caspase-3 dependent proteolytic cleavage of protein kinase Cdelta (PKCdelta) that not only mediates apoptosis in dopaminergic cells, but also influences key cellular events such as amplification of the apoptotic cascade through positive feedback activation and hyperphosphorylation of alpha-synuclein. We will extend our preliminary findings by pursuing the following Specific Aims: (I) characterize mitochondrial dysfunction and the subsequent activation sequence of key proapoptotic factors during dieldrin-induced oxidative stimulation in the mesencephalic dopaminergic cell model of Parkinson's disease, (ii) establish the proapoptotic function of caspase-3 dependent proteolytic activation of PKC5 in Dieldrin induced dopaminergic degeneration and to further investigate mechanisms underlying positive feedback amplification of the apoptotic signaling cascade by PKCdelta, (iii) obtain evidence to support the hypothesis that proteolytically activated PKCdelta hyperphosphorylates alpha-synuclein and thereby promotes protein aggregation, (iv) examine whether chronic exposure to Dieldrin in animal models induces caspase-3 dependent proteolytic cleavage of PKCdelta, alpha-synuclein aggregation, Lewy body formation and apoptotic cell death of dopaminergic neurons in the substantia nigra, and finally, (v) confirm the involvement of PKCdelta in nigral dopaminergic degeneration by using PKCdelta knockout animals and by targeted over-expression of PKCdelta and alpha-synuclein using a lentiviral delivery system in animal models. Together, results from the proposed systematic investigation will demonstrate the involvement of mitochondrial dysfunction, oxidative stress, apoptosis and protein aggregation in dopaminergic degeneration, and will further illuminate the mechanistic role of environmental factors in PD pathogenesis.
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