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Nigrostriatal neuronal death in Parkinson’s disease — a passive or an active genetically-controlled process?

  • I. Ziv
  • A. Barzilai
  • D. Offen
  • N. Nardi
  • E. Melamed
Conference paper

Summary

The cause for the rather selective degeneration of the nigrostriatal dopaminergic (DA) neurons in Parkinson’s disease (PD) is still enigmatic. The major current hypothesis suggests that nigral neuronal death in PD is due to excessive oxidant stress generated by auto- and enzymatic oxidation of DA, formation of neuromelanin and presence of high concentrations of iron. Such cell death is generally regarded as a passive, necrotic process, mainly resulting from membrane lipid peroxidation, leading to its dysfunction and rupture and then to neuronal disintegration.

We suggest a novel approach, that views neuronal degeneration in PD as an active process that occurs mainly the nuclear level. Our concept is based on the following observations: (1) Nigral histopathology in PD is characterized by a slow, protracted degeneration of individual neurons. We propose that it may be due to apoptosis [programmed cell-death (PCD), an active, genetically-controlled, intrinsic program of cell “suicide”] rather than to necrotic cell death. (2) DA exerts antitumor effect on melanoma and neuroblastoma cells. (3) Many anticancer drugs, trigger PCD by causing DNA damage. (4) DA has been shown to be genotoxic. (5) We recently first showed that DA, the endogenous neurotransmitter in the nigra, can trigger apoptosis in cultured, postmitotic sympathetic neurons. (6) We have also shown that PC-12 cells, transfected with the bcl-2 gene (a proto-oncogene that inhibits PCD) are relatively resistant to DA-apoptotic effect.

Degeneration of nigrostriatal neurons in PD may therefore be linked to dysregulation of the control mechanisms that normally restrain the PCD-triggering-potential of their own neurotransmitter.

Keywords

Sympathetic Neuron Excessive Oxidant Stress Selective Degeneration Nigrostriatal Neuron Incidental Lewy Body Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Barinaga M (1993) Death gives birth to the nervous system. But how? Science 259:762–763PubMedGoogle Scholar
  2. Boobis AR, Fawthrop DJ, Davies DS (1989) Mechanisms of cell death. Trends Pharmacol Sci 10: 275–280PubMedCrossRefGoogle Scholar
  3. Bursch W, Oberhammer F, Sculte-Hermann R (1992) Cell death by apoptosis and its protective role against disease. Trends Pharmacol Sci 13: 245–251PubMedCrossRefGoogle Scholar
  4. Cohen JJ (1993) Apoptosis. Immunol Today 14: 126–130PubMedCrossRefGoogle Scholar
  5. Eastman A (1990) Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells 2: 275–280PubMedGoogle Scholar
  6. Fahn S, Cohen G (1992) The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 32: 804–812PubMedCrossRefGoogle Scholar
  7. Garcia I, Martinou I, Tsushimoto Y, Martinou JC (1992) Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science 258: 302–304PubMedCrossRefGoogle Scholar
  8. Graham DJ, Tiffany SM, Bell WR, Gutknecht WF (1978) Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward cl300 neuroblastoma cells in vitro. Mol Pharmacol 14:644–653PubMedGoogle Scholar
  9. Hirsch EC (1992) Why are nigral catecholaminergic neurons more vulnerable than other cells in Parkinson’s disease? Ann Neurol 32: S88–S93PubMedCrossRefGoogle Scholar
  10. Jenner P, Dexter DT, Sian J (1992) Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. Ann Neurol 32: S82–S87PubMedCrossRefGoogle Scholar
  11. Lin LFH, Doherty DH, Lile JD (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260: 1131–1132Google Scholar
  12. Martin DP, Schmidt RE, Distefano PS, Johnson EN (1988) Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by NGF deprivation. J Cell Biol 106: 829–843PubMedCrossRefGoogle Scholar
  13. Michel PP, Hefti F (1990) Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture. J Neurosci Res 26: 428–435PubMedCrossRefGoogle Scholar
  14. Moldeus P, Nordenskjold M, Bolcsfoldi G (1983) Genetic toxicity of dopamine. Mut Res 124: 9–23.CrossRefGoogle Scholar
  15. Olanow CW (1993) A radical hypothesis for neurodegeneration. Trends Neurosci 16:439–444PubMedCrossRefGoogle Scholar
  16. Orrenius S, Burkitt M, Kass GEN (1992) Calcium ions and oxidative cell injury. Ann Neurol 32: S33–S42PubMedCrossRefGoogle Scholar
  17. Robbins Jh, Otsuka F, Nee LE (1985) Parkinson’s disease and Alzheimer’s disease: hypersensitivity to x-rays in cultured cell lines. J Neurol Neurosurg Psychiatry 48: 916–923PubMedCrossRefGoogle Scholar
  18. Schraufstatter IU, Hyslop PA, Hinshaw DB (1986) Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly (ADP-ribose) polymerase. Proc Natl Acad Sci 83: 4908–4912PubMedCrossRefGoogle Scholar
  19. Scudiero DA, Tarone RE, Robbins JH (1982) Parkinson’s disease and Alzheimer’s disease fibroblasts are hypersensitive to killing by MNNG. Clin Res 30: 857(A)Google Scholar
  20. Tooyama I, Kawamata T, Walker D, Mcgeer PL (1993) Loss of basic fibroblast growth factor in substantia nigra neurons in Parkinson’s disease. Neurology 43: 372–376PubMedGoogle Scholar
  21. Ueda N, Shah SV (1992) Endonuclease-induced DNA damage and cell death in oxidant injury to renal tubular epithelial cells. J Clin Invest 90: 2593–2597PubMedCrossRefGoogle Scholar
  22. Wick MM (1978) Dopamine: a novel antitumor agent active against B-16 melanoma in vivo. J Invest Dermatol 71: 163–164PubMedGoogle Scholar
  23. Wick MM (1980) Levodopa and dopamine analogs as DNA polymerase inhibitors and antitumor agents in humsn melanoma. Cancer Res 40: 1414–1418PubMedGoogle Scholar
  24. Wick MM (1989) Levodopa/dopamine analogs as inhibitors of DNA synthesis in human melanoma cells. J Invest Dermatol 92: 329S–331SPubMedCrossRefGoogle Scholar
  25. Wyllie AH (1980) Glucocorticocoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284: 555–557PubMedCrossRefGoogle Scholar
  26. Ziv I, Melamed E, Nardi N, Luria D, Achiron A, Offen D, Barzilai A (1994) Dopamine induces apoptosis-like cell death in cultured sympathetic neurons — a possible novel pathogenetic mechanism in Parkinson’s disease. Neurosci Lett 170: 136–140PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1997

Authors and Affiliations

  • I. Ziv
    • 1
  • A. Barzilai
    • 2
  • D. Offen
    • 1
  • N. Nardi
    • 2
  • E. Melamed
    • 1
  1. 1.Department of Neurology and Felsenstein Research InstituteBeilinson Medical CenterPetah-TiqvaIsrael
  2. 2.Department of Biochemistry, The George Wise Faculty of Life SciencesNeuroscience, Tel-Aviv UniversityTel-AvivIsrael

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