DOPAMINE-INDUCED APOPTOSIS IS INHIBITED IN PC12 CELLS EXPRESSING BCL-2

1. Degeneration of nigrostriatal dopaminergic neurons is the major pat hogenic substrate of Parkinson's disease (PD). It is assumed that the lethal trigger is the accumulation of oxidative reactive species gener ated during metabolism of the natural neurotransmitter dopamine. 2. We have recently shown that dopamine is capable of inducing programmed c ell death (PCD) or apoptosis in cultured postmitotic chick sympathetic neurons and rat PC12 pheochromocytoma cells. 3. The bcl-2 gene encode s a protein which blocks physiological PCD in many mammalian cells. In an attempt to elucidate further the mechanism of dopamine toxicity, w e examined the potential protective effect of bcl-2 in PC12 cells whic h were transfected with the protooncogene. 4. In our experiments, Bcl- 2 producing cells showed a marked resistance to dopamine toxicity. The percentage of nuclear condensation and DNA fragmentation visualized b y the end-labeling method following dopamine treatment was significant ly lower in bcl-2 expressing cells. Bcl-2 did not protect PC12 cells a gainst toxicity induced by exposure to dopamine-melanin. Extracts of P C12 cells containing Bcl-2 inhibited dopamine autooxidation and format ion of dopamine-melanin. Furthermore, the presence of Bcl-2 protected cells from thiol imbalance and prevented thiol loss following exposure to dopamine. 5. The protective effects of Bcl-2 against dopamine toxi city may be explained, in part, by its action as an antioxidant and by its interference in the production of toxic agents. The possible prot ection by Bcl-2 against neuronal degeneration caused by dopamine may p lay a role in the pathogenesis of PD and may provide a new direction f or the development of neuroprotective therapies.