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Iron storage and transport markers in Parkinson’s disease and MPTP-treated mice

  • D. C. Mash
  • J. Singer
  • J. Pablo
  • M. Basile
  • J. Bruce
  • W. J. Weiner
Conference paper
Part of the Key Topics in Brain Research book series (KEYTOPICS)

Summary

The regulation of neuronal iron is necessary for the synthesis of iron containing cytochromes and to prevent damage from free radicals by iron-oxygen interactions. We have shown that transferrin receptors are elevated over the substantia nigra in the human and rat brain (Mash et al., 1990) and are depleted concomitantly with dopaminergic terminals in the MPTP-treated mouse striatum (Mash et al., 1991). Given the iron dependency for both synthetic and degradative enzyme activities, dopaminergic neurons may express transferrin receptors on their cell surface to facilitate the uptake of iron bound to transferrin. If the intracellular iron pool is regulated by receptor-mediated transferrin uptake, then an up-regulation of transferrin receptor number may play a role in the pathogenesis of nigral cell damage in Parkinson’s disease. Early in the disease process, surviving dopaminergic neurons may increase the number of transferrin receptors in order to meet the increased metabolic demand associated with compensatory changes in dopamine synthesis and turnover. The uptake of ferrotransferrin by dopaminergic neurons may result in a progressive elevation in the cellular iron load that exceeds the regulatory capacity for increased ferritin expression in the aging brain.

Keywords

Substantia Nigra Progressive Supranuclear Palsy Iron Storage Transferrin Receptor Brain Iron 
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. Aldred A, Dickson P, Marley P, Schreiber G (1987) Distribution of transferring synthesis in brain and other tissues of the rat. J Biol Chem 262: 5293–5297PubMedGoogle Scholar
  2. Barbeau A (1984) Manganese and extrapyramidal disorders a critical review and tribute to Cotzias, George C. Neurotoxicology 5: 13–35PubMedGoogle Scholar
  3. Birchall J, Chappell J (1988) Aluminum, chemical physiology and Alzheimer’s disease. Lancet 11: 1008–1010CrossRefGoogle Scholar
  4. Boyd D, Vecoli C, Belcher D, Jain S, Drysdale J (1985) Structural and functional relationships of human ferritin H and L chains deduced from cDNA clones. J Biol Chem 260: 11755–11761PubMedGoogle Scholar
  5. Connor J, Phillips T, Lakshman M, Barron K, Fine R, Csiza C (1987) Regional variation in the levels of transferrin in the CNS of normal and myelin deficient rats. J Neurochem 49: 1523–1529PubMedCrossRefGoogle Scholar
  6. Conner J, Benkovic S (1992) Iron regulation in the brain: histochemical, biochemical and molecular considerations. Ann Neurol 32: 551–561CrossRefGoogle Scholar
  7. Dexter D, Wells F, Lees A (1987) Increased nigral iron content in post-mortem parkinsonian brain. Lancet ii: 1219–1220Google Scholar
  8. Dexter D, Carter F, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden C (1989) Increased nigral iron content and alterations in other metal ions occuring in brain in Parkinson’s disease. J Neurochem 52: 1830–1836PubMedCrossRefGoogle Scholar
  9. Dexter D, Jenner P, Schapira A, Marsden C (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. Ann Neurol 32: S94 — S100PubMedCrossRefGoogle Scholar
  10. Dickson P, Aldred A, Marley P, Guo-Fen T, Howlett G, Schreiber G (1985) High prealbumin and transferrin mRNA levels in the choroid plexus of rat brain. Biochem Biophys Res Commun 127: 890–895PubMedCrossRefGoogle Scholar
  11. Donaldson J, Barbeau A (1985) Manganese neurotoxicity: possible clues to the etiology of human brain disorders. In: Neurology and neurobiology, vol 15. Metal ions in neurology and psychiatry. Liss, New York, pp 259–285Google Scholar
  12. Dreosti I, Smith R (1983) Neurobiology of trace elements, vol 1. Humana, Clifton NJ, pp 269–291Google Scholar
  13. Drysdale J, Alpert E (1975) Human isoferritins–reply. Br J Haem 30: 518–519CrossRefGoogle Scholar
  14. Duguid J, De La Paz R, DeGroot J (1986) Magnetic resonance imaging of the midbrain in Parkinson’s disease. Ann Neurol 20: 744–747PubMedCrossRefGoogle Scholar
  15. Dwork A, Schon E, Herbert J (1988) Nonidentical distribution of transferrin and ferric iron in human brain. Neuroscience 27: 333–345PubMedCrossRefGoogle Scholar
  16. Götz M, Freyberger A, Riederer P (1990) Oxidative stress: a role in the pathogenesis of Parkinson’s disease. J Neural Transm [Suppl] 29: 241–249Google Scholar
  17. Halliwell B (1987) Oxidants and human disease: some new concepts. Fed Am Soc Exp Biol 892: 358–364Google Scholar
  18. Halliwell B, Gutteridge J (1986) Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Mol Aspects Med 8: 89–193CrossRefGoogle Scholar
  19. Hill J (1988) Brain iron: neurochemical and behavioral aspects. Taylor and Francis, London, pp 1–24Google Scholar
  20. Hill J, Ruff M, Weber R, Pert C (1985) Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron. Proc Natl Acad Sci USA 82: 4553–4557PubMedCrossRefGoogle Scholar
  21. Hirsch E, Brandel J, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an x-ray microanalysis. J Neurochem 56: 446–451PubMedCrossRefGoogle Scholar
  22. Hock A, Demmel U, Schicha H, Kasperek K, Feinendegen L (1975) Trace element concentration in human brain. Brain 98: 49–64PubMedCrossRefGoogle Scholar
  23. Huebers H, Finch C (1987) The physiology of transferrin and transferrin receptors. Physiol Rev 67: 520–582PubMedGoogle Scholar
  24. Irwin I, DeLaney L, Forno L, Finnegan K, Di Monte D, Langston J (1989) The evolution of nigrostriatal neurochemical changes in the MPTP-treated squirrel monkey. Brain Res 531: 242–252CrossRefGoogle Scholar
  25. Jefferies W, Brandon M, Hunt 5, Williams A, Gatters K, Masons D (1984) Transferrin receptor on endothelium of brain capillaries. Nature 312: 162–163 Joshi JGoogle Scholar
  26. Zimmerman A (1988) Ferritin: an expanded role in metabolic regulation. Toxicology 48: 21–29PubMedCrossRefGoogle Scholar
  27. Kish S, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease: pathophysiological and clinical implications. N Engl J Med 318: 876–880PubMedCrossRefGoogle Scholar
  28. Kitt C, Cork L, Eidelberg F, John T, Price D (1986) Injury of nigral neurons exposed to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine: a tyrosine hydroxylase immunocytochemical study in monkey. Neuroscience 17: 1089–1103PubMedCrossRefGoogle Scholar
  29. Koeppen A, Dentinger M (1988) Brain hemosiderin and superficial siderosis of the central nervous system. J Neuropathol Exp Neurol 47: 249–270PubMedCrossRefGoogle Scholar
  30. Koeppen A, Hurwitz C, Dearborn R, Dickson A, Borke R, Chu R (1992) Experimental superficial siderosis of the central nervous system: biochemical correlates. J Neurol Sci 112: 38–45PubMedCrossRefGoogle Scholar
  31. Kopin I, Markey S (1988) MPTP toxicity: implications for research in Parkinson’s disease. Ann Rev Neurosci 11: 81–96PubMedCrossRefGoogle Scholar
  32. Mash D, Pablo J, Flynn D, Efange S, Weiner W (1990) Characterization and localization of transferrin receptors in the rat brain. J Neurochem 55: 1972–1979PubMedCrossRefGoogle Scholar
  33. Mash D, Pablo J, Buck B, Sanchez-Ramos J, Weiner W (1991) Distribution and number of transferrin receptors in Parkinson’s disease and in MPTP-treated mice. Exp Neurol 114: 73–81PubMedCrossRefGoogle Scholar
  34. Morris C, Candy J, Bloxham C, Edwardson J (1990) Brain transferrin receptorsand the distribution of cytochrome oxidase. Biochem Soc Trans 18: 647PubMedGoogle Scholar
  35. Morris C, Candy J, Keith A, Oakley A, Taylor G, Pullen G, Bloxham C, Gocht A, Edwardson J (1992) Brain iron homeostasis. J Inorg Biochem 47: 257–265PubMedCrossRefGoogle Scholar
  36. Norfray J, Couch J, Elble R, Good D, Manyam B, Patrick J (1988) Visualization of brain iron by mid-field MR. Am J Neurorad 9: 77–82Google Scholar
  37. Olanow C (1992) An introduction to the free radical hypothesis in Parkinson’s disease. Ann Neurol 32: 52–59CrossRefGoogle Scholar
  38. Reinhard J, Miller D, O’Callaghan J (1988) The neurotoxicant MPTP (1-methyl4-phenyl-1,2,3,6-tetrahydropyridine) increases glial fibrillary acidic protein and decreases dopamine levels of the striatum: evidence for glial response to injury. Neurosci Lett 95: 246–251PubMedCrossRefGoogle Scholar
  39. Ricaurte G, Langston J, Delanney L, Irwin I, Peroutka S, Forno L (1986) Fate of nigrostriatal neurons in young mature mice given 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine: a neurochemical and morphological reassessment. Brain Res 375: 117–124Google Scholar
  40. Ricaurte G, Delanney L, Irwin I, Langston J (1987) Older dopaminergic neurons do not recover from the effects of MPTP. Neuropharmacology 26: 97–99PubMedCrossRefGoogle Scholar
  41. Riederer P, Sofic E, Rausch W, Schmidt B, Reynolds G, Jellinger K, Youdim M (1989) Transitional metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52: 515–520PubMedCrossRefGoogle Scholar
  42. Roskams A, Connor J (1990) Aluminum access to the brain: a possible role for the transferrin receptor. Proc Natl Acad Sci USA 87: 9024–9027PubMedCrossRefGoogle Scholar
  43. Rutledge J, Hilal S, Silver A, Defendini R, Fahn S (1987) Study of movement disorders and brain iron by MR. Am J Neurorad 8: 397–411Google Scholar
  44. Sonsalla P, Heikkila R (1986) The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. Eur J Pharmacol 129: 339–345PubMedCrossRefGoogle Scholar
  45. Sternlieb I (1984) Wilson’s disease: indication for liver transplants. Hepatology 4: 515–517CrossRefGoogle Scholar
  46. Swaiman K, Machen V (1986) Iron uptake by mammalian cortical neurons. Ann Neurol 16: 66–70CrossRefGoogle Scholar
  47. Tennison M, Bouldin M, Whaley R (1988) Mineralization of the basal ganglia detected by CT in Hallervorden-Spatz syndrome. Neurology 38: 154–155PubMedGoogle Scholar
  48. Theil E (1990) Regulation of ferritin and transferrin receptor mRNAs. J Biol Chem 265 (9): 4771–4774PubMedGoogle Scholar
  49. Wang J, Huang C, Hwang Y, Chiang J, Lin J, Chen J (1989) Manganese induced parkinsonism: an outbreak due to an unrepaired ventilation control system in a ferromanganese smelter. Br J Ind Med 46: 856–859PubMedGoogle Scholar
  50. Willis G, Donnan G (1987) Histochemical, biochemical and behavioral consequences of MPTP treatment in C-57 black mice. Brain Res 402: 269–274PubMedCrossRefGoogle Scholar
  51. Youdim M, Ben-Shachar D, Riederer P (1989) Is Parkinson’s disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? Acta Neurol Scand 126: 47–54CrossRefGoogle Scholar
  52. Youdim M, Ben-Shachar D, Yehuda Y, Riederer P (1990) The role of iron in the basal ganglion. Adv Neurol 53: 155–161PubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1993

Authors and Affiliations

  • D. C. Mash
    • 1
    • 2
  • J. Singer
    • 1
  • J. Pablo
    • 1
  • M. Basile
    • 1
  • J. Bruce
    • 3
  • W. J. Weiner
    • 1
  1. 1.Department of NeurologyUniversity of Miami School of MedicineMiamiUSA
  2. 2.Department of Molecular and Cellular PharmacologyUniversity of Miami School of MedicineMiamiUSA
  3. 3.Department of PathologyUniversity of Miami School of MedicineMiamiUSA

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