THE PROTOONCOGENE BCL-2 INHIBITS CELLULAR TOXICITY OF DOPAMINE - POSSIBLE IMPLICATIONS FOR PARKINSONS-DISEASE

It is currently believed that excessive oxidant stress induced by meta bolism of dopamine (DA), plays a major role in the pathogenesis of the selective nigrostriatal neuronal loss in Parkinson's disease, We rece ntly showed that the neurotransmitter CA, in physiological concentrati ons, is capable of initiating apoptosis in cultured, post-mitotic symp athetic neurons, Bcl-2 is a proto-oncogene that blocks apoptosis. We n ow report that Bcl-2 is a powerful inhibitor of DA toxicity in PC-12 p heochromocytoma cells, We induced stable expression of Bcl-2 in PC-12 cells by transfection with recombinant pCMV5 expression vector, contai ning mouse bcl-2 (coding-sequence) cDNA. Cells expressing Bcl-2 manife sted marked resistance to otherwise lethal (300 uM) in vitro concentra tions of DA, This protective effect was reflected in the trypan-blue t est of cell survival, H-3-thymidine incorporation and inhibition of th e characteristic apoptotic morphologic alterations in scanning electro n microscopic studies, Bcl-2 and associated control systems of apoptos is may have an important physiological role in restraining the apoptos is-triggering potential of CA in nigrostriatal neurons, This novel fie ld of research may yield insights into the pathogenesis of Parkinson's disease and lead to development of novel therapeutic approaches.