Activation of p53 signaling initiates apoptotic death in a cellular model of Parkinson's disease.
Mitochondrial dysfunction caused by oxidative stress and genetic defects have been implicated in the loss of dopaminergic neurons in Parkinson's disease. However, the key molecular events that provoke neurodegeneration still remain poorly understood. We recently showed that shortly after exposure to oxidative stress, only those cells showing phosphorylation of p53 at Ser-15 subsequently undergo active cell death. To investigate the role of this early p53 signaling response in cell death, 6-hydroxydopamine was used to induce oxidative stress in dopaminergic neurons generated from embryonic stem cells and PC12-D(2)R cells. Exposure to toxic concentrations of 6-hydroxydopamine induced phosphorylation of p53 at Ser-15 even before cells show mitochondrial permeabilization and apoptosis. We found that 6-hydroxydopamine induced phosphorylation of ataxia telangiectasia mutated (ATM) kinase an event integral to p53 activation and caffeine (ATM kinase inhibitor) inhibited Ser-15 phosphorylation. Phosphorylation of Ser-15 was correlated with enhanced induction and functional activation of p53 manifest as transcription of the pro-apoptotic p53 target Puma. Moreover, inhibition of the p53 abrogated the induction of Puma and promotion of apoptosis due to 6-hydroxydopamine treatments. Thus, these data suggest that activation of p53 signaling immediately after neurotoxin exposure acts as an initiating factor to mediate apoptosis in dopaminergic cells.
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. Venugopalan.Nair@mssm.edu
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D051379:Mice; D009474:Neurons / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013565:Sympatholytics / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D013565:Sympatholytics; D016159:Tumor Suppressor Protein p53; D016627:Oxidopamine