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Activation of p53 signaling initiates apoptotic death in a cellular model of Parkinson’s disease

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Abstract

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-D2R 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.

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Abbreviations

PD:

Parkinson’s disease;

SNc:

substantia nigra pars compacta;

6-OHDA:

6-hydroxydopamine

ES:

embryonic stem cells;

EB:

embryoid body;

DA:

dopamine;

TH:

tyrosine hydroxylase;

DAT:

dopamine transporter;

Tuj1:

β-tubulin type III;

ERK:

extracellular regulated kinase;

FGF:

fibroblast growth factor;

AA:

ascorbic acid;

MPTP:

N-methyl-4-phenyl-1,2,3,6-tetrahydroyridine;

PFT-α :

pifithrin alpha

ATM:

Ataxia Telangiectasia Mutated

References

  1. Nair VD, Yuen T, Olanow CW, Sealfon SC. Early single cell bifurcation of pro- and antiapoptotic states during oxidative stress. J Bio Chem 2004; 279: 27494–27501.

    Article  CAS  Google Scholar 

  2. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: An etiologic study. JAMA 1999; 281: 341–346.

    Article  PubMed  CAS  Google Scholar 

  3. Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 2003; 302: 819–822.

    Article  PubMed  CAS  Google Scholar 

  4. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000; 3: 1301–1306.

    Google Scholar 

  5. Burns RS, Chiueh CC, Markey SP, et al. A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc Natl Acad Sci USA 1983; 80: 4546–4550.

    Article  PubMed  CAS  Google Scholar 

  6. Glinka YY, Youdim MB. Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. Eur J Pharmacol 1995; 292: 329–332.

    PubMed  CAS  Google Scholar 

  7. Beal MF. Experimental models of Parkinson’s disease. Nat Rev Neurosci 2001; 2: 325–334.

    Article  PubMed  CAS  Google Scholar 

  8. Dauer W, Przedborski S. Parkinson’s disease: Mechanisms and models. Neuron 2003; 39: 889–909.

    Article  PubMed  CAS  Google Scholar 

  9. Graham DG, Tiffany SM, Bell WR, Jr., Gutknecht WF. Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 1978; 14: 644–653.

    PubMed  CAS  Google Scholar 

  10. Dodel RC, Du Y, Bales KR, et al. Caspase-3-like proteases and 6-hydroxydopamine induced neuronal cell death. Brain Res Mol Brain Res 1999; 64: 141–148.

    Article  PubMed  CAS  Google Scholar 

  11. Lotharius J, Dugan LL, O’Malley KL. Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. J Neurosci 1999; 19: 1284–1293.

    PubMed  CAS  Google Scholar 

  12. Han BS, Hong HS, Choi WS, et al. Caspase-dependent and -independent cell death pathways in primary cultures of mesencephalic dopaminergic neurons after neurotoxin treatment. J Neurosci 2003; 23: 5069–5078.

    PubMed  CAS  Google Scholar 

  13. Ding YM, Jaumotte JD, Signore AP, Zigmond MJ. Effects of 6-hydroxydopamine on primary cultures of substantia nigra: Specific damage to dopamine neurons and the impact of glial cell line-derived neurotrophic factor. J Neurochem 2004; 89: 776–787.

    Article  PubMed  CAS  Google Scholar 

  14. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408: 307–310.

    Article  PubMed  CAS  Google Scholar 

  15. Morrison RS, Kinoshita Y. The role of p53 in neuronal cell death. Cell Death Differ 2000; 7: 868–879.

    Article  PubMed  CAS  Google Scholar 

  16. Duan W, Zhu X, Ladenheim B, et al. p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Ann Neurol 2002; 52: 597–606.

    Article  PubMed  CAS  Google Scholar 

  17. Mandir AS, Simbulan-Rosenthal CM, Poitras MF, et al. A novel in vivo post-translational modification of p53 by PARP-1 in MPTP-induced parkinsonism. J Neurochem 2002; 83: 186–192.

    Article  PubMed  CAS  Google Scholar 

  18. Blum D, Wu Y, Nissou MF, et al. p53 and Bax activation in 6-hydroxydopamine-induced apoptosis in PC12 cells. Brain Res 1997; 751: 139–142.

    Article  PubMed  CAS  Google Scholar 

  19. Trimmer PA, Smith TS, Jung AB, Bennett JP, Jr. Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 1996; 5: 233–239.

    Article  PubMed  CAS  Google Scholar 

  20. Nagy A, Rossant J, Nagy R, et al. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci USA 1993; 90: 8424–8428.

    Article  PubMed  CAS  Google Scholar 

  21. Lee SH, Lumelsky N, Studer L, et al. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 2000; 18: 675–679.

    Article  PubMed  CAS  Google Scholar 

  22. Okabe S, Forsberg-Nilsson K, Spiro AC, et al. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 1996; 59: 89–102.

    Article  PubMed  CAS  Google Scholar 

  23. Johe KK, Hazel TG, Muller T, et al. Single factors direct the differentiation of stem cells from the fetal and adult nervous system. Genes Dev 1996; 10: 3129–3140.

    PubMed  CAS  Google Scholar 

  24. Nair VD, Olanow W, Sealfon SC. Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines. Biochem J 2003; 373: 25–32.

    Article  PubMed  CAS  Google Scholar 

  25. Nair VD, Sealfon SC. Agonist specific transactivation of phosphoinositide 3-kinase signaling pathway mediated by the dopamine D2 receptor. J Biol Chem 2003; 278: 47053–47061.

    Article  CAS  Google Scholar 

  26. Douhou A, Troadec JD, Ruberg M, et al. Survival promotion of mesencephalic dopaminergic neurons by depolarizing concentrations of K+ requires concurrent inactivation of NMDA or AMPA/kainate receptors. J Neurochem 2001; 78: 163–174.

    Article  PubMed  CAS  Google Scholar 

  27. Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease.Nature 2002; 418: 50–56.

    Article  PubMed  CAS  Google Scholar 

  28. Shim JW, Koh HC, Chang MY, et al. Enhanced in vitro midbrain dopamine neuron differentiation, dopaminergic function, neurite outgrowth, and 1-methyl-4-phenylpyridium resistance in mouse embryonic stem cells overexpressing Bcl-XL. J Neurosci 2004; 24: 843–852.

    Article  PubMed  CAS  Google Scholar 

  29. Hartmann A, Hunot S, Michel PP, et al. Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci USA 2000; 97: 2875–2880.

    Article  CAS  Google Scholar 

  30. Mogi M, Togari A, Kondo T, et al. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J Neural Transm 2000; 107: 335–341.

    Article  PubMed  CAS  Google Scholar 

  31. Elkon H, Melamed E, Offen D. Oxidative stress, induced by 6-hydroxydopamine, reduces proteasome activities in PC12 cells: Implications for the pathogenesis of Parkinson’s disease. J Mol Neurosci 2004; 24: 387–400.

    Article  PubMed  CAS  Google Scholar 

  32. Shieh SY, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1997; 91: 325–334.

    Article  PubMed  CAS  Google Scholar 

  33. Komarov PG, Komarova EA, Kondratov RV, et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 1999; 285: 1733–1737.

    Article  PubMed  CAS  Google Scholar 

  34. Culmsee C, Zhu X, Yu QS, et al. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem 2001; 77: 220–228.

    Article  PubMed  CAS  Google Scholar 

  35. Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003; 302: 1036–1038.

    Article  PubMed  CAS  Google Scholar 

  36. Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003; 11: 577–590.

    Article  PubMed  CAS  Google Scholar 

  37. Chipuk JE, Kuwana T, Bouchier-Hayes L, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004; 303: 1010–1014.

    Article  PubMed  CAS  Google Scholar 

  38. Harris SL, Levine AJ. The p53 pathway: Positive and negative feedback loops. Oncogene 2005; 24: 2899–2908.

    Article  PubMed  CAS  Google Scholar 

  39. Canman CE, Lim DS, Cimprich KA, et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998; 281: 1677–1679.

    Article  PubMed  CAS  Google Scholar 

  40. Chen K, Albano A, Ho A, Keaney JF, Jr. Activation of p53 by oxidative stress involves PDGFbeta receptor-mediated ATM kinase activation. J Biol Chem 2003.

  41. Fornstedt B, Rosengren E, Carlsson A. Occurrence and distribution of 5-S-cysteinyl derivatives of dopamine, dopa and dopac in the brains of eight mammalian species. Neuropharmacology 1986; 25: 451–454.

    Article  PubMed  CAS  Google Scholar 

  42. Blum D, Torch S, Lambeng N, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001; 65: 135–172.

    Article  PubMed  CAS  Google Scholar 

  43. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995; 268: 1749–1753.

    PubMed  CAS  Google Scholar 

  44. Green MH, Marcovitch AJ, Harcourt SA, et al. Hypersensitivity of ataxia-telangiectasia fibroblasts to a nitric oxide donor. Free Radic Biol Med 1997; 22: 343–347.

    Article  PubMed  CAS  Google Scholar 

  45. Chen P, Peng C, Luff J, et al. Oxidative stress is responsible for deficient survival and dendritogenesis in purkinje neurons from ataxia-telangiectasia mutated mutant mice. J Neurosci 2003; 23: 11453–11460.

    PubMed  CAS  Google Scholar 

  46. Canman CE, Lim DS, Cimprich KA, et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998; 281: 1677–1679.

    Article  PubMed  CAS  Google Scholar 

  47. Morrison RS, Kinoshita Y, Johnson MD, et al. p53-dependent cell death signaling in neurons. Neurochem Res 2003; 28: 15–27.

    Article  PubMed  CAS  Google Scholar 

  48. Owen-Schaub LB, Zhang W, Cusack JC, et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 1995; 15: 3032–3040.

    PubMed  CAS  Google Scholar 

  49. Muller M, Wilder S, Bannasch D, et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 1998; 188: 2033–2045.

    Article  PubMed  CAS  Google Scholar 

  50. Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288: 1053–1058.

    Article  PubMed  CAS  Google Scholar 

  51. Yu J, Zhang L, Hwang PM, et al. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 2001; 7: 673–682.

    Article  PubMed  CAS  Google Scholar 

  52. Schuler M, Bossy-Wetzel E, Goldstein JC, et al. p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J Biol Chem 2000; 275: 7337–7342.

    Article  PubMed  CAS  Google Scholar 

  53. Tibbetts RS, Brumbaugh KM, Williams JM, et al. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev 1999; 13: 152–157.

    PubMed  CAS  Google Scholar 

  54. Liang SH, Clarke MF. Regulation of p53 localization. Eur J Biochem 2001; 268: 2779–2783.

    Article  PubMed  CAS  Google Scholar 

  55. Zhang Y, Xiong Y. A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 2001; 292: 1910–1915.

    Article  PubMed  CAS  Google Scholar 

  56. Biswas SC, Ryu E, Park C, et al. Puma and p53 play required roles in death evoked in a cellular model of Parkinson disease. Neurochem Res 2005; 30: 839–845.

    Article  PubMed  CAS  Google Scholar 

  57. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7: 683–694.

    Article  PubMed  CAS  Google Scholar 

  58. Daily D, Barzilai A, Offen D, et al. The involvement of p53 in dopamine-induced apoptosis of cerebellar granule neurons and leukemic cells overexpressing p53. Cell Mol Neurobiol 1999; 19: 261–276.

    Article  CAS  Google Scholar 

  59. Tanaka Y, Engelender S, Igarashi S, et al. Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 2001; 10: 919–926.

    Article  PubMed  CAS  Google Scholar 

  60. Saha AR, Ninkina NN, Hanger DP, et al. Induction of neuronal death by alpha-synuclein. Eur J Neurosci 2000; 12: 3073–3077.

    Article  PubMed  CAS  Google Scholar 

  61. da Costa CA, Masliah E, Checler F. Beta-synuclein displays an antiapoptotic p53-dependent phenotype and protects neurons from 6-hydroxydopamine-induced caspase 3 activation: Cross-talk with alpha-synuclein and implication for Parkinson’s disease. J Biol Chem 2003; 278: 37330–37335.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029

    V. D. Nair Ph.D

  2. Department of Neurology, Mount Sinai School of Medicine, Box 1137, Annenberg 14-72, One Gustave L. Levy Place, New York, NY, 10029

    V. D. Nair Ph.D

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Correspondence to V. D. Nair Ph.D.

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Nair, V.D. Activation of p53 signaling initiates apoptotic death in a cellular model of Parkinson’s disease. Apoptosis 11, 955–966 (2006). https://doi.org/10.1007/s10495-006-6316-3

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