The mechanisms underlying the pathogenesis of many neurodegenerative diseases remain elusive. Though still debated, most studies have concluded that aging, environmental neurotoxin exposures, and genetic alterations are potential risk factors in the evolution of dopaminergic degenerative disorders, including Parkinson's disease. It is believed that environmental factors accelerate the normal aging process and thereby predispose the dopaminergic system to the chronic neurodegenerative condition. Among the myriad of environmental risk factors, exposure to transition metals has been shown to cause perturbation in normal cellular processes through oxidative stress-mediated mechanisms. It is well documented that chronic exposure to the transition metal manganese induces a Parkinson's-like syndrome in humans. The recent legalization of an organic manganese compound, methylcyclopentadienyl manganese tricarbonyl (MMT), for use as a gasoline additive in the United States raises serious health concerns in our aging society. In preliminary studies, the investigators have shown that MMT causes dopaminergic neurodegeneration in cultured neuronal cells. The objectives of the current proposal are (i) to characterize the dopaminergic neurotoxicity of MMT in several in vitro models of Parkinson's disease, (ii) to evaluate the effect of MMT on oxidative stress and Ca2+ load, and their contribution to dopaminergic degeneration, (iii) to define the cell death pathways leading to apoptosis, including: opening of the mitochondrial permeability transition pore, modulation of Bcl2/Bax, release of cytochrome-C, activation of caspases, MAP kinases and PLA2, translocation of redox sensitive transcription factors, namely NFkappaB and AP-1, and over-expression of inducible target genes, namely NOS-2 and COX-2, (iv) to compare the differential activation of cell death factors underlying dopaminergic neurodegeneration in young and aged rats following long-term MMT exposure, and finally, (v) to examine whether genetic or pharmacological modulation of over-expression of target genes NOS-2 and COX-2 attenuates the dopaminergic degeneration induced by MMT. Together, this systematic approach should lead to significant advances in our understanding of the causative role of MMT in selective dopaminergic neurodegeneration.
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