The molecular and biochemical mode of cell death of dopaminergic neurons in Parkinson's disease (PD) is uncertain. In an attempt at further clarification we studied the effects of 1-methyl-4-phenylpyridinium (MPP + ), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on dopaminergic PC12 cells. In humans and nonhuman primates MPTP/MPP + causes a syndrome closely resembling PD. MPP + toxicity is thought to be mediated by the block of complex I of the mitochondrial electron transport chain. Treatment of undifferentiated PC12 cells with MPP + primarily inhibited proliferation of PC12 cells and secondarily led to cell death after the depletion of all 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 inhibition 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 cyclin-dependent kinase inhibitor p21 WAF1/Cip1 and growth arrest. Since treatment with 1 μM MPP + caused apoptotic cell death in p21 WAF1/Cip1 -deficient (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 finally leads to a nonapoptotic cell death.
Experimental Cell Research – Elsevier
Published: Jul 10, 1999
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