Dopaminergic cell death in Parkinson’s disease: a role of iron?

  • F. Javoy-Agid
  • B. Faucheux
Conference paper
Part of the Key Topics in Brain Research book series (KEYTOPICS)


Loss of midbrain dopaminergic neurons in Parkinson’s disease is associated to hyperoxidation phenomena. In the human substantia nigra, free radicals may be produced in large quantities i.e, during degradation of dopamine, synthesis and accumulation of neuromelanin, through iron, present in high concentrations. Under normal conditions, production of free radicals is compensated by powerful protective enzymes: superoxide dismutase is detected in neurons, and expressed at high levels in those of the substantia nigra; gluthatione peroxidase is exclusively detected in glial cells. A low density of glial cells surround the substantia nigra neurons relatively to other midbrain areas. Thus nigral dopaminergic neurons may be less protected against deleterious action of free radicals. This may explain their preferential susceptibility to oxidative stress. In Parkinson’s disease, an overproduction of free radicals, suggested by the increased level of lipid peroxidation in the substantia nigra, might accelerate the rate of dopaminergic cells death. Impairment of the oxygen toxicity protective mechanisms may be responsible. Besides, the above normal levels of iron in the substantia nigra may contribute to free radical production and have a role in the toxic process, though one cannot exclude the increased iron content may be a non-specific product of cellular degeneration, a consequence of the gliosis.


Substantia Nigra Dopaminergic Neuron Ventral Tegmental Area Progressive Supranuclear Palsy Midbrain Dopaminergic Neuron 
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  1. Agid Y, Javoy-Agid F, Ruberg M (1987) Biochemistry of neurotransmitters in Parkinson’s disease. In: Marsden CD, Fahn S (eds) Movement disorders, vol 2. Butterworth, London, pp 166–230Google Scholar
  2. Ambani LM, Van Voert MH, Murphy S (1975) Brain peroxidase and catalase in Parkinson’s disease. Arch Neurol 32: 114–118PubMedCrossRefGoogle Scholar
  3. Barbeau A (1984) Manganese and extrapyramidal disorders (a critical review and tribute to Dr. Georges C. Cotzias). Neurotoxicoloy 5: 13–36Google Scholar
  4. Ben-Shachar D, Riederer P, Youdim MBH (1991) Iron-melanin interaction and lipid peroxidation: implications for Parkinson’s disease. J Neurochem 57: 1609–1614PubMedCrossRefGoogle Scholar
  5. Birchall JD, Cappell JS (1988) Aluminium, chemical physiology and Alzheimer’s disease. Lancet ii: 1008–1010Google Scholar
  6. Blin J, Bonnet, AM, Vidailhet M, Brandabur M, Agid Y (1991) Does aging aggravate parkinsonian disability? J Neurol Neurosurg Psychiatry 54: 780–782PubMedCrossRefGoogle Scholar
  7. Bomford AB, Munro HN (1985) Transferrin and its receptors: their roles in cell function. Hepathology 5: 870–875CrossRefGoogle Scholar
  8. Ceballos I, Lafon M, Javoy-Agid F, Hirsch E, Nicole A, Sinet PM, Agid Y (1990) Superoxide dismutase and Parkinson’s disease. Lancet is 1035–1036Google Scholar
  9. Damier P, Hirsch E, Javoy-Agid F, Zhang P, Agid Y (1993) Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52: 1–6PubMedCrossRefGoogle Scholar
  10. Dexter D, Carter C, Javoy-Agid F, Lees AJ, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 52: 381–389PubMedCrossRefGoogle Scholar
  11. Dexter DT, Carayon A, Javoy-Agid F, Agid Y Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114: 1953–1975PubMedCrossRefGoogle Scholar
  12. Duvoisin RC (1986) Etiology of Parkinson’s disease: current concepts. Clin Neuropharmacol [Suppl 1]: S3 — S11Google Scholar
  13. Earle KM (1968) Studies on Parkinson’s disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27: 1— 14Google Scholar
  14. Faucheux BA, Hirsch EC, Villares J, Selimi F, Mouatt-Prigent A, Javoy-Agid F, Hauw JJ, Agid Y (1993) Distribution of ferrotransferrin binding sites in the mesencephalon of control subjects and patients with Parkinson’s disease. J Neurochem 60: 2338–2341PubMedCrossRefGoogle Scholar
  15. Forno LS (1982) Pathology of Parkinson’s disease. In: Marsden CD, Fahn S (eds) Movement disorders. Butterworth, London, pp 25–40Google Scholar
  16. Gibb WRG, Lees AJ (1991) Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 54: 388–396PubMedCrossRefGoogle Scholar
  17. Graham DG (1979) On the origin and significance of neuromelanin. Arch Pathol Lab Med 103: 359–362PubMedGoogle Scholar
  18. Graham DG, Tiffany SM, Bell WR (1978) Auto-oxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds towards C 1300 neuroblastoma cells in vitro. Mol Pharmacol 14: 644–65 3Google Scholar
  19. Hallgren B, Sourander P (1958) The effect of age on non haemin iron in human brain. J Neurochem 3: 41–51PubMedCrossRefGoogle Scholar
  20. Halliwell B, Gutteridge JMC (1986) Iron and free radical reactions: two aspects of antioxidant protection. Trends Biol Sci 11: 1372–1375CrossRefGoogle Scholar
  21. Hassler R (1938) Zur Pathologie der Paralysis agitans and des postencephalitischen Parkinsonismus. J Psychol Neurol 48: 387–476Google Scholar
  22. Hirsch EC, Graybiel AM, Agid Y (1988) Melanized dopaminergic neurons are differentially affected in Parkinson’s disease. Nature 334: 345–348PubMedCrossRefGoogle Scholar
  23. Hirsch EC, Brandel JP, Galleg P, Javoy-Agid F, Agid Y (1991) Iron and aluminium increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56: 446–451PubMedCrossRefGoogle Scholar
  24. Hirsch EC, Mouatt A, Faucheux B, Bonnet AM, Javoy-Agid F, Graybiel A, Agid Y (1992) Dopamine, tremor and Parkinson’s disease. Lancet is 340: 125–126CrossRefGoogle Scholar
  25. Jellinger K (1986) Pathology of parkinsonism. In: Fahn S, Marsden CD, Jenner P, Teychenne P (eds) Recent development in Parkinson’s disease. Raven Press, New York, pp 303–307Google Scholar
  26. Johnson WG, Hodge SE, Duvoisill R (1990) Twin studies and the genetic of Parkinson’s disease — a reappraisal. Mov Disord 53: 187–194CrossRefGoogle Scholar
  27. Kastner A, Hirsch EC, Lejeune O, Javoy-Agid F, Rascol O, Agid Y (1993) Is the vulnerability of neurons in the substantia nigra of patients with Parkinson’s disease related to their neuromelanin content? J Neurochem 59: 1080–1092CrossRefGoogle Scholar
  28. Koller W, Vetere-Overfield B, Gray RN, Alexander BS, Chin T, Dolezal J, Hassanein R, Tanner C (1990) Environmental risk factors in Parkinson’s disease. Neurology 40: 1218–1221PubMedGoogle Scholar
  29. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of mepedrine analogue synthesis. Science 219: 979–980PubMedCrossRefGoogle Scholar
  30. Mann DMA, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech Ageing Dev 21: 193–203PubMedCrossRefGoogle Scholar
  31. Marsden CD (1983) Neuromelanin and Parkinson’s disease. J Neural Transm [Suppl] 19: 121–141Google Scholar
  32. Marttila RJ, Lorentz H, Rinne UK (1988) Oxygen toxicity protecting enzymes in Parkinson’s disease. J Neurol Sci 86: 321–331PubMedCrossRefGoogle Scholar
  33. Mc Geer PL, Mc Geer EC, Suzuki J (1977) Aging and extrapyramidal function. Arch Neurol 34: 33–35CrossRefGoogle Scholar
  34. Mc Geer PL, Itagaki Q, Akiyama H, Mc Geer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24: 564–576CrossRefGoogle Scholar
  35. Perry TL, Yong WW (1986) Idiopathic Parkinson’s disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci Lett 67: 269–274PubMedCrossRefGoogle Scholar
  36. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MBH (1989) Transition metals, ferritin, glutathione and ascorbic acid in parkinsonian brains. J Neurochem 52: 515–520PubMedCrossRefGoogle Scholar
  37. Saggu H, Cooksey J, Dexter D, Wells FR, Lees A, Jenner P, Marsden CD (1989) A selective increase in particulate superoxide dismutase activity in parkinsonian substantia nigra. J Neurochem 53: 692–697PubMedCrossRefGoogle Scholar
  38. Scheinberg IH, Strenlief I (1984) Wilson’s disease. Saunders, Philadelphia Schermann D, Desnos C, Darchen F, Pollak P, Javoy-Agid F, Agid Y (1989)Google Scholar
  39. Striatal dopamine deficiency in Parkinson’s disease: role of aging. Ann Neurol 26: 551–557Google Scholar
  40. Youdim MBH, Ben-Shachar D (1989) Iron-melanin interaction in substantia nigra as the neurotoxic component of Parkinson’s disease. II International Conference “Basic and Therapeutic Strategies XX Alzheimer’s and Parkinson’s disease” Kyoto, Japan (Abstracts, p 53 )Google Scholar
  41. Zhang P, Damier P, Hirsch EC, Agid Y, Ceballos-Picot I, Sinet PM, Nicole A, Laurent M, Javoy-Agid F (1993) Preferential expression of superoxide dismutase messenger RNA in melanized neurons in human mesencephalon. Neuroscience 55: 167–175PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1993

Authors and Affiliations

  • F. Javoy-Agid
    • 1
  • B. Faucheux
    • 1
  1. 1.Hôpital de la SalpêtrièreINSERM U 289ParisFrance

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