1-METHYL-4-PHENYLPYRIDINUM KILLS DIFFERENTIATED PC12 CELLS WITH A CONCOMITANT CHANGE IN PROTEIN-PHOSPHORYLATION

1-Methyl-4-phenylpyridinum (MPP(+)), a selective neurotoxin, destroys the dopaminergic nigrostriatal pathway and results in a parkinsonian s yndrome. Exposure of differentiated PC12 cells with nerve growth facto r for 5 days to MPP(+) (100 mu M) for 4 h induced DNA fragmentation wh ich is typical for the programmed cell death. MPP(+) treatment (100 mu M) concomitantly stimulates S6 kinase activity and resultant phosphor ylation of S6 protein of 40S ribosomal subunits in the cells. Cyclohex imide treatment prevents the MPP(+)-induced DNA fragmentation and enha ncement of the phosphorylation of S6 protein. The present data demonst rate that neurotoxin, MPP(+), kills differentiated PC12 cells by the a pparent involvement of apoptotic process. Furthermore, the data strong ly suggest that a change in protein phosphorylation might be involved in the signal transduction of MPP(+) neurotoxicity and/or the protecti on from its toxicity.