MPP+ inhibits proliferation of PC12 cells by a p21(WAF1/Cip1)-dependent pathway and induces cell death in cells lacking p21(WAF1/Cip1)

The molecular and biochemical mode of cell death of dopaminergic neurons in Parkinson's disease (PD) is uncertain. In an attempt at further clarificat ion we studied the effects of 1-methyl-4-phenylpyridinium (MPP+), the activ e metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on dop aminergic PC12 cells. In humans and nonhuman primates MPTP/MPP+ causes a sy ndrome closely resembling PD, MPP+ toxicity is thought to be mediated by th e block of complex I of the mitochondrial electron transport chain. Treatme nt of undifferentiated PC12 cells with MPP+ primarily inhibited proliferati on of PC12 cells and secondarily led to cell death after the depletion of a ll energy substrates by glycolysis. This cell death showed no morphological characteristics of apoptosis and was not blocked by treatment with caspase inhibitors. The inhibition of cell growth was not dependent on an inhibiti on of complex I activity since MPP+ also inhibited cell proliferation in SH -SY5Y cells lacking mitochondrial DNA and complex I activity (p(0) cells). As shown by flow cytometric analysis, MPP+ induced a block in the G(0)/G(1) to S phase transition that correlated with increased expression of the cyc lin-dependent kinase inhibitor p21(WAF1/Cip1) and growth arrest. Since trea tment with 1 mu M MPP+ caused apoptotic cell death in p21(WAF1/Cip1)-defici ent (p21(-/-)) but not in parental (p21(+/+)) mouse embryo fibroblasts, our data suggest that in an early phase MPP+-induced p21(WAF1/Cip1) expression leads to growth arrest and prevents apoptosis until energy depletion final ly leads to a nonapoptotic cell death. (C) 1999 Academic Press.