Cellular and Molecular Neurobiology, Vol. 19, No. 2, 1999 The Involvement of p53 in Dopamine-Induced Apoptosis of Cerebellar Granule Neurons and Leukemic Cells Overexpressing p53 Dvorah Daily, 1 Ari Barzilai, 1,3 Daniel Offen, 2 Ariel Kamsler, 1 Eldad Melamed, 2 and Ilan Ziv 2 Received January 7, 1998; accepted May 5, 1998 SUMMARY 1. The pathogenesis of the selective degeneration of the dopaminergic neurons in Parkinson’s disease is still enigmatic. Recently we have shown that dopamine can induce apoptosis in postmitotic neuronal cells, as well as in other cellular systems, thus suggesting a role for this endogenous neurotransmitter and associated oxidative stress in the neuronal death process. 2. Dopamine has been shown to be capable of inducing DNA damage through its oxidative metabolites. p53 is a transcription factor that has a major role in determining cell fate in response to DNA damage. We therefore examined the possible correlation between dopamine-triggered apoptosis, DNA damage and levels of total phosphorylated p53 protein in cultured mouse cerebellar granule neurons. 3. Marked DNA damage and apoptotic nuclear condensation and fragmentation were detected within several hours of exposure to dopamine. An associated marked threefold increase in p53 phosphorylation was observed within this time window. Using a tempera- ture-sensitive p53 activation system in leukemia LTR6 cells, were found that p53 inactiva- tion dramatically attenuated dopamine toxicity. 4. We therefore conclude that DNA damage and p53 activation may have a role in mediating dopamine-induced apoptosis. Modulation of the p53 system may therefore have a protective role against the toxicity of this endogenous neurotransmitter and associated oxidative stress. KEY WORDS: Parkinson’s disease; catecholamines; oxidative metabolites; phosphoryla- tion; DNA damage; apoptosis; p53. 1 Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel. 2 Department of Neurology and Felsenstein Research Institute, Beilinson Medical Center and the Sackler School of Medicine, Tel Aviv University Ramat Aviv, Tel Aviv 69978 Israel. 3 To whom correspondence should be addressed. 261 0272-4340/99/0400–0261$16.00/0  1999 Plenum Publishing Corporation