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Proteolytic cleavage of PKCdelta is essential for MMT-induced apoptosis in dopaminergic cells



Proteolytic cleavage of PKCdelta is essential for MMT-induced apoptosis in dopaminergic cells



Society for Neuroscience Abstracts 26(1-2): Abstract No -381 11



We have previously shown that Methylcyclopentadienyl Manganese Tricarbonyl (MMT, a gasoline additive) induces oxidative stress-mediated cell death in dopaminergic cells. To further understand the molecular mechanisms underlying MMT-induced dopaminergic degeneration, we examined the effects of MMT on apoptotic cell signaling molecules in both rat pheochromocytoma (PC12) and immortalized rat mesencephalic (1RB3AN27) cell lines. Exposure to MMT (50-500 muM) over 3h period resulted in a dose- and time-dependent proteolytic cleavage of PKCdelta to yield 41 kD catalytic and 38 kD regulatory fragments. Additionally, MMT exposure (1 hr) resulted in a dramatic increase (>15-fold) in Caspase 3 activity. Pretreatment with Ac-DEVD-CHO (100 muM), a caspase 3-specific inhibitor, almost completely blocked the MMT-induced PKCdelta cleavage. Pretreatment with 10 muM rottlerin, a PKCdelta inhibitor, blocked MMT induced increase in Caspase 3 activity by more than 50%. These results suggest that Caspase 3 activation occurs both upstream and down stream of PKCdelta cleavage possibly via a positive feedback mechanism. MMT treatment produced a dose-dependent increase in apoptosis as determined by FACScan analysis. Pretreatment with 10 muM rottlerin reduced the apoptotic cell population by more than 60%. Together these results, for the first time, suggest that MMT is capable of inducing a programmed cell death in dopaminergic cells by activating caspase 3-dependent PKCdelta cleavage, and further indicate that environmental exposure to MMT may contribute to the evolution of Parkinson's disease.

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