Summary
Histopathological, biochemical and in vivo brain imaging techniques, such as magnetic resonance imaging and transcranial sonography, revealed a consistent increase of substantia nigra (SN) iron in Parkinson’s disease (PD). Increased iron deposits in the SN may have genetic and non-genetic causes. There are several rare movement disorders associated with neurodegeneration, and genetic abnormalities in iron regulation resulting in iron deposition in the brain. Non-genetic causes of increased SN iron may be the result of a disturbed or open blood-brain-barrier, local changes in the normal iron-regulatory systems, intraneuronal transportation of iron from iron-rich area into the SN and release of iron from intracellular iron storage molecules. Major iron stores are ferritin and haemosiderin in glial cells as well as neuromelanin in neurons. Age- and disease dependent overload of iron storage proteins may result in iron release upon reduction. Consequently, the low molecular weight chelatable iron complexes may trigger redox reactions leading to damage of biomolecules. Additionally, upon neurodegeneration there is strong microglial activation which can be another source of high iron concentrations in the brain.
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References
Aisen P, Leibman A (1972) Lactoferrin and transferrin: a comparative study. Biochem Biophys Acta 257: 314–323
Aisen P, Wessling-Resnick M, Leibold EA (1999) Iron metabolism. Curr Opin Chem Biol 3: 200–206
Anderson BF, Baker HM, Norris GE, Rice DW, Baker EN (1989) Structure of human lactoferrin: crystal-lographic structure analysis and refinement at 2.8A resolution. J Molec Biol 209: 711–734
Andrew R, Watson DG, Bet SA, Midgley JM, Wenlong H, Perry RK (1993) The determination of 6-hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls. Neurochem Res 18: 1175–1177
Berg D, Gerlach M, Youdim MBH, Double KL, Zecca L, Riederer P, Becker G (2001) Brain iron pathways and their relevance to Parkinson’s disease. J Neurochem 79: 225–236
Biemond P, Van Eijk H, Swaak A, Koster J (1984) Iron mobilisation from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes: possible mechanism in inflammation diseases. J Clin Invest 73: 1576–1579
Birgens HS (1991) The interaction of lactoferrin with human monocytes. Dan Med Bull 38: 244–252
Boyer RE, Grabill T, Petrovich R (1988) Reactive release of ferritin iron: a kinetic assay. Anal Biochem 174: 17–22
Connor JR, Menzies SL, Martin SM, Mufson EJ (1990) Cellular distribution of transferrin, ferritin and iron in normal and aged human brains. J Neurosci Res 27: 595–611
Connor J, Synder BS, Beard JL, Fine R, Mufson, E (1992) Regional distribution of iron and ironregulatory proteins in the brain in aging and Alzheimer’s disease. J Neurosci Res 31: 327–335
Connor JR, Boeshore KL, Benkovic SA, Menzies SL (1994) Isoforms of ferritin have a specific cellular distribution in the brain. J Neurosci Res 37: 461–465
Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt P (1995) A quantitative analysis of isoferritins in selected regions of aged, parkinsonian and Alzheimer’s diseased brains. J Neurochem 65: 717–724
Davidson LA, Lonnerdal B (1989) Fe-saturation and proteolysis of human lactoferrin: effect on brushborder receptor mediated uptake of Fe and Mn. Am J Physiol 2257: G930–G934
Dexter DT, Carayon A, Vihailhet M, Ruberg M, Agid F, Agid Y, Lees AJ, Wells FR, Jenner P, Marsden CD (1990) Decreased ferritin levels in brain of Parkinson’s disease. J Neurochem 55: 16–20
Double KL, Maywald M, Schmittel M, Riederer P, Gerlach M (1998) In vitro studies of ferritin iron release and neurotoxicity. J Neurochem 70: 2492–2499
Double KL, Riederer P, Gerlach M (1999) The significance of neuromelanin for neurodegeneration in Parkinson’s disease. Drug News Perspect 12: 333–340
Double KL, Gerlach M, Youdim MBH, Riederer P (2000) Impaired iron homeostasis in Parkinson’s disease. J Neural Transm [Suppl] 60: 37–58
Double KL, Gerlach M, Schünemann V, Trautwein AX, Zecca L, Gallorini M, Youdim MBH, Riederer P, Ben-Shachar D (2003) Iron binding characteristics of neuromelanin of the human substantia nigra. Biochem Pharmacol 66: 489–494
Dwork A, Lawler G, Zybert P, Durkin M, Osman M, Willson N, Barkai A (1990) An autoradiographic study of the uptake and distribution of iron by the brain of young rat. Brain Res 518: 31–39
Faucheux BA, Nillesse N, Damier P, Spik G, Mouatt-Prigent A, Pierce A, Leveugle B, Kubis N, Hauw JJ, Agid Y, Hirsch EC (1995) Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson’s disease. Proc Natl Acad Sci USA 92: 9603–9607
Faucheux BA, Hauw J, Agid Y, Hirsch EC (1997) The density of [125I]-transferrin binding sites on perikarya of melanized neurons of the substantia nigra is decreased in Parkinson’s disease. Brain Res 749: 170–174
Federow H, Tribl F, Halliday G, Gerlach M, Riederer P, Double K (2005) Neuromelanin in human dopamine neurons: comparison with pheripheral melanins and relevance to Parkinson’s disease. Progr Neurobiol 75: 109–124
Fillebeen C, Descamps L, Dehouck MP, Fenart L, Benaissa M, Spik G, Cecchelli R, Pierce A (1999a) Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J Biol Chem 274: 7011–7017
Fillebeen C, Mitchell V, Dexter D, Benaissa M, Beauvillain JC, Spik G, Pierce A (1999b) Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. Mol Brain Res 72: 183–194
Gerlach M, Ben-Shachar D, Riederer P, Youdim MBH (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 63: 793–807
Gerlach M, Trautwein AX, Zecca L, Youdim MBH, Riederer P (1995) Mössbauer spectroscopic studies of human neuromelanin isolated from the substantia nigra. J Neurochem 65: 923–926
Gerlach M, Double K, Götz ME, Youdim MBH, Riederer P (2006) The role of iron in the pathogenesis of Parkinson’s disease. In: Sigel A, Sigel H, Sigel RKO (eds) Neurodegenerative Diseases and Metal Ions, Vol 1 of Metal Ions in Life Sciences. Wiley & Sons, Chichester (in press)
Good P, Olanow C, Perl D (1992) Neuromelanincontaining neurons of the substantia nigra accumulate iron and aluminum in Parkinson’s disease: a LAMMA study. Brain Res 593: 343–346
Götz ME, Double K, Gerlach M, Youdim MBH, Riederer P (2004) The relevance of iron in the pathogenesis of Parkinson’s disease. Ann NYAcad Sci 1012: 193–208
Hallgren B, Sourander P (1958) The effect of age on non-haem iron in the human brain. J Neurochem 3: 41–51
Halliwell B, Gutteridge JM (1986) Iron and free radical reactions: two aspects of antioxidant protection. Trends Biochem Sci 11: 1372–1375
He Y, Thong PS, Lee T, Leong SK, Mao BY, Dong F, Watt F (2003) Dopaminergic cell death precedes iron elevation in MPTP-injected monkeys. Free Rad Biol Med 35: 540–547
Hirsch E, Graybiel A, Agid Y (1988) Melanized dopamine neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334: 345–348
Hu J, Connor J (1996) Demonstration and characterization of the iron regulatory protein in human brain. J Neurochem 67: 838–844
Jellinger K (1989) Pathology of Parkinson’s syndrome. In: Calne DB (eds) Handbook of experimental pharmacology, vol 88. Springer, Berlin Heidelberg, pp 47–112
Jellinger K, Paulus W, Grundke-Iqbal I, Riederer P, Youdim MBH (1990) Brain iron and ferritin in Parkinson’s disease and Alzheimer’s disease. J Neural Transm [PD Sect] 2: 327–340
Jellinger K, Kienzel E, Rumpelmair G, Riederer P, Stachellberger H, Ben-Shachar D, Youdim MBH (1992) Iron-melanin complex in substantia nigra of parkinsonian brains: an X-ray microanalysis. J Neurochem 59: 1168–1171
Jellinger K, Linert L, Kienzl E, Herlinger E, Youdim MBH (1995) Chemical evidence for 6-hydroxy-dopamine to be an endogenous toxic factor in the pathogenesis of Parkinson’s disease. J Neural Transm [Suppl] 46: 297–314
Kienzl E, Puchinger L, Jellinger K, Linert W, Stachelberger H, Jameson R (1995) The role of transition metals in the pathogenesis of Parkinson’s diease. J Neurol Sci 134: 69–78
Kortekaas R, Leenders KL, van Oostrom JCH, Vaalburg W, Bart J, Willemsen ATM, Hendrikse NH (2005) Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 57: 76–179
Lapenna D, Degioia S, Ciofani G, Cuccurullo F (1995) Captopril induces iron release from ferritin and oxidative stress. J Pharm Pharmacol 47: 59–61
Leveugle B, Faucheux B, Bouras C, Nillesse N, Spik G, Hirsch E, Agid Y, Hof P (1996) Cellular distribution of the iron-binding protein lactoferrin in the mesencephalon of Parkinson’s disease cases. Acta Neuropathol 91: 566–572
Linert W, Herlinger E, Jameson RF, Kienzl E, Jellinger K, Youdim MBH (1996) Dopamine, 6-hydroxydopamine, iron and dioxygen — their mutual interactions and possible implication in the development of Parkinson’s disease. Biochim Biophys Acta [Molec Basis Dis] 1316: 160–168
Logroscino G, Marder K, Graziano J, Freyer G, Slavkovich V, LoIacono N, Cote L, Mayeux R (1997) Altered systemic iron metabolism in Parkinson’s disease. Neurology 49: 714–717
Lopiano L, Digilio G, Fasano M, Giraudo S, Rizzone M, Torre E, Bergamasco B (1999) Iron and neuromelanin in Parkinson’s disease. J Neural Transm 106: XXIV
Mann VM, Cooper JM, Daniel SE, Srai K, Jenner P, Marsden CD, Schapira AH (1994) Complex I, iron, and ferritin in Parkinson’s disease substantia nigra. Ann Neurol 36: 876–881
Meneghini R (1997) Iron homeostasis, oxidative stress and DNA damage. Free Radic Biol Med 23: 783–792
Monteiro HP, Winterbourn CC (1989) 6-Hydroxydopamine releases iron from ferritin and promotes ferritin-dependent lipid peroxidation. Biochem Pharmacol 38: 4177–4182
Morris C, Candy J, Omar S, Bloxham C, Edwardson J (1994) Transferrin receptors in the parkinsonian midbrain. Neuropathol Appl Neurobiol 20: 468–472
Napolitano A, Crescenzi O, Pezzella A, Prota G (1995) Generation of the neurotoxin 6-hydroxydopamine by peroxidase/H2O2 oxidation of dopamine. J Med Chem 38: 917–922
Oestreicher E, Sengstock GJ, Riederer P, Olanow CW, Dunn AJ, Arendash GW (1994) Degeneration of nigrostriatal dopaminergic neurons increases iron within the substantia nigra: a histochemical and neurochemical study. Brain Res 660: 8–18
Ponka P (1999) Cellular iron metabolism. Kidney Int [Suppl 69] 55: 2–11
Riederer P (2004) Views on neurodegeneration as a basis for neuroprotective strategies. Med Sci Monit 10(12): RA287–RA290
Riederer P, Sofic E, Rausch WD, Kruzik P, Youdim MBH (1985) Dopaminforschungheute undmorgen — L-Dopa in der Zukunft. In: Riederer P, Vmek H (eds) L-Dopa-Substitution der Parkinson-Krankheit. Geschichte-Gegenwart-Zukunft. Springer, Wien New York, pp 127–144
Riederer P, Rausch WD, Schmidt B, Kruzik C, Sofic E, Danielczyk W, Fischer M, Ogris E (1988) Biochemical fundamentals of Parkinson’s disease. Mt Sinai J Med 55: 21–28
Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52: 515–520
Rief D, Simmons R (1990) Nitric oxide mediates iron release from ferritin. Arch Biochem Biophys 283: 537–541
Schipper HM (2000) Heme oxygenase-1, role in brain ageing and neurodegeneration. Exp Gerontol 35: 821–830
Schipper HM (2004) Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med 37: 1995–2011
Sian J, Gerlach M, Youdim MBH, Riederer P (1999) Parkinson’s disease: a major hypokinetic basal ganglia disorder. J Neural Transm 106: 443–476
Shima T, Sarna T, Swartz H, Stroppolo A, Gerbasi R, Zecca L (1997) Binding of iron to neuromelanin of human substantia nigra and synthetic melanin: an electron paramagnetic resonance spectroscopy study. Free Radic Biol Med 23: 110–119
Smith MA, Wehr K, Harris PLR, Siedlak SL, Connor JR, Perry G (1998) Abnormal localisation of iron regulatory protein in Alzheimer’s disease. Brain Res 788: 232–236
Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MBH (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74: 199–205
Sofic E, Paulus W, Jellinger K, Riederer P, Youdim MBH (1991) Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 56: 978–982
Thomas M, Jankovic J (2004) Neurodegenerative disease and iron storage in the brain. Curr Opin Neurol 17: 437–442
Thomson A, Rogers J, Leedman P (1999) Iron regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int J BiochemCell Biol 31: 1139–1152
Torsdottir G, Kristinsson J, Sveinbjornsdottier S, Snaedal J, Jahannesson T (1999) Copper, ceruloplasmin, superoxide dismutase and iron parameters in Parkinson’s disease. Pharmacol Toxicol 85: 239–243
Yamada Y, Amagasaki T, Jacobsen DW, Green R (1987) Lactoferrin binding by leukemia cell lines. Blood 70: 264–270
Yoshida T, Tanaka M, Sotomatsu A, Hirai S (1995) Activated microglia cause superoxide-mediated release of iron from ferritin. Neurosci Lett 190: 21–24
Youdim MBH, 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 [Suppl 126] 80: 47–54
Youdim M, Ben-Shachar D, Riederer P (1993) The possible role of iron in the etiopathology of Parkinson’s disease. Mov Disord 8: 1–12
Zecca L, Swartz HM (1993) Total and paramagnetic metals in human substantia nigra and its neuromelanin. J Neural Transm [PD Sect] 5: 203–213
Zecca L, Shima T, Stroppolo A, Goj C, Battiston A, Gerbasi R, Sarna T, Swartz HM (1996) Interaction of neuromelanin and iron in substantia nigra and other areas of human brain. Neuroscience 73: 407–415
Zecca L, Youdim MBH, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5: 863–873
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Gerlach, M., Double, K.L., Youdim, M.B.H., Riederer, P. (2006). Potential sources of increased iron in the substantia nigra of parkinsonian patients. In: Riederer, P., Reichmann, H., Youdim, M.B.H., Gerlach, M. (eds) Parkinson’s Disease and Related Disorders. Journal of Neural Transmission. Supplementa, vol 70. Springer, Vienna . https://doi.org/10.1007/978-3-211-45295-0_21
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DOI: https://doi.org/10.1007/978-3-211-45295-0_21
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