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Brain iron metabolism and its perturbation in neurological diseases

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Abstract

Enormous advances have been made in the last decade in understanding iron metabolism and iron homeostasis at both the cellular and the systemic level. This includes the identification of genes and proteins involved in iron transport, such as the ferric reductase DcytB, the proton-coupled ferrous (divalent) iron transporter DMT1, the iron exporter ferroportin and the membrane-bound ferroxidase hephaestin. The modulation of their translation by the iron regulatory protein (IRP) system has also been identified together with the impressive signalling cascades involved in regulating the chef d’orchestre of systemic iron homeostasis, hepcidin. However, exactly how the brain regulates fluxes and storage of iron between neurons, oligodendrocytes, astrocytes and microglial cells remains an enigma. In this review we discuss the possible mechanisms which may be involved in the transfer of iron across the blood–brain barrier(BBB), together with the possible role played by astrocytes. The consequences of iron deficiency and iron excess on brain function are described. Finally, various neurodegenerative diseases, where accumulation of iron may be important in the pathogenesis, are presented as well as the possible use of iron chelators to diminish disease progression.

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Notes

  1. 1.

    Other proteins with functional IREs in their 5′-UTR include hypoxia inducible factor 2a [99], erythroid aminolaevulinate synthase and mitochondrial aconitase (reviewed in [100]), and more recently amyloid precursor protein [101].

References

  1. Crichton RR (2008) Biological chemistry, an introduction. Elsevier, Amsterdam, p 369

    Google Scholar 

  2. Ohgami RS, Campagne DR, McDonald A, Fleming MD (2006) Blood 108:1388

    Article  PubMed  CAS  Google Scholar 

  3. Moos T, Oates PS, Morgan EH (1998) J Comp Neurol 31:420

    Article  Google Scholar 

  4. Moos T, Morgan EH (2002) Dev Neurosci 24:99

    Article  PubMed  CAS  Google Scholar 

  5. Rouault TA, Cooperman S (2006) Semin Pediatr Neurol 13:142

    Article  PubMed  Google Scholar 

  6. Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR (2001) J Neurosci Res 66:1198

    Article  PubMed  CAS  Google Scholar 

  7. Moos T, Morgan EH (2004) J Neurochem 88:233

    Article  PubMed  CAS  Google Scholar 

  8. Moos T, Rosengren Nielsen T (2006) Semin Pediatr Neurol 13:149

    Article  PubMed  Google Scholar 

  9. Moos T, Skjoerringe T, Gosk S, Morgan EH (2006) J Neurochem 98:1946

    Article  PubMed  CAS  Google Scholar 

  10. Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H (2008) Nature 455:992

    Article  PubMed  CAS  Google Scholar 

  11. Moos T, Rosengren Nielsen T, Skj½rringe T, Morgan EH (2007) J Neurochem 103:1730

    Article  PubMed  CAS  Google Scholar 

  12. Morgan EH (1977) Biochim Biophys Acta 499:169

    Article  PubMed  CAS  Google Scholar 

  13. Morgan EH (1979) Biochim Biophys Acta 580:312

    Article  PubMed  CAS  Google Scholar 

  14. Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004) Brain Res 1001:108

    Article  PubMed  CAS  Google Scholar 

  15. Fischer J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA, Connor JR (2007) Am J Physiol Cell Physiol 293:C641

    Article  CAS  Google Scholar 

  16. Mills E, Dong X-P, Wang F, Xu H (2010) Future Med Chem 2:51

    Article  PubMed  CAS  Google Scholar 

  17. Lane DJR, Robinson SR, Czerwinska H, Bishop GM, Lawen A (2011) Biochem J 432:123–132

    Google Scholar 

  18. Jeong SY, David S (2003) J Biol Chem 278:27144

    Article  PubMed  CAS  Google Scholar 

  19. De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, Kaplan J (2007) EMBO J 26:2823

    Article  PubMed  CAS  Google Scholar 

  20. Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR (2009) Glia 57:467

    Article  PubMed  Google Scholar 

  21. Ward RJ, Crichton RR, Taylor DL, Corte LD, Srai SK, Dexter DT (2010) J Neural Transm. doi:10.1007/s00702-010-0479-3

  22. Dallman PR, Beutler E, Finch CA (1978) Br J Haematol 40:179

    Article  PubMed  CAS  Google Scholar 

  23. Dallman PR, Siimes MA, Stekel A (1980) Am J Clin Nutr 33:86

    PubMed  CAS  Google Scholar 

  24. Beard JL (2008) J Nutr 138:2534

    PubMed  CAS  Google Scholar 

  25. Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T (2006) Nutr Rev 64:S34

    Article  PubMed  Google Scholar 

  26. Rao R, Georgieff MK (2007) Semin Fetal Neonatal Med 12:54

    Article  PubMed  Google Scholar 

  27. Rao R, Tkac I, Townsend EL, Gruetter R, Georgieff MK (2003) J Nutr 133:3215

    PubMed  CAS  Google Scholar 

  28. Rao R, Tkac I, Townsend EL, Ennis K, Gruetter R, Georgieff MK (2007) J Cerebr Blood Flow Metab 27:872

    Article  Google Scholar 

  29. Ward KL, Tkac I, Jing Y, Felt B, Beard J, Connor J, Schallert T, Georgieff MK, Rao R (2007) J Nutr 137:1043

    PubMed  CAS  Google Scholar 

  30. Beard JL, Wiesinger JA, Connor JR (2003) Dev Neurosci 25:308

    Article  PubMed  CAS  Google Scholar 

  31. Ortiz E, Pasquini JM, Thompson K, Felt B, Butkus G, Beard J, Connor JR (2004) J Neurosci Res 77:681

    Article  PubMed  CAS  Google Scholar 

  32. Beard J, Erikson KM, Jones BC (2003) J Nutr 133:1174

    PubMed  CAS  Google Scholar 

  33. Burhans MS, Dailey C, Beard Z, Wiesinger J, Murray-Kolb L, Jones BC, Beard JL (2005) Nutr Neurosci 8:31

    Article  PubMed  CAS  Google Scholar 

  34. Bradbury MWB (1997) J Neurochem 67:443

    Google Scholar 

  35. G–tz ME, Double K, Gerlach M, Youdim MB, Riederer P (2004) Ann N Y Acad Sci 1012:193

    Article  CAS  Google Scholar 

  36. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Nat Rev Neurosci 5:863

    Article  PubMed  CAS  Google Scholar 

  37. Biasiotto G, Goldwurm S, Finazzi D, Tunesi S, Zecchinelli A, Sironi F, Pezzoli G, Arosio P (2008) Parkinsonism Relat Disord 14:426

    Article  PubMed  Google Scholar 

  38. Bartzokis G, Lu PH, Tishler TA, Peters DG, Kosenko A, Barrall KA, Finn JP, Villablanca P, Laub G, Altshuler LL, Geschwind DH, Mintz J, Neely E, Connor JR (2010) J Alzheimers Dis 20:333

    PubMed  CAS  Google Scholar 

  39. Goodhall EF, Greenway MJ, van Marion I, Carrol CB, Hardiman O, Morrison KE (2005) Neurology 65:934

    Article  CAS  Google Scholar 

  40. Johnstone D, Milward EA (2010) J Neurochem 113:1387

    PubMed  CAS  Google Scholar 

  41. Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG (2007) Hepatology 46:1071

    Article  PubMed  CAS  Google Scholar 

  42. Penke L, Valdés Hernandéz MC, Maniega SM, Gow AJ, Murray C, Starr JM, Bastin ME, Deary IJ, Wardlaw JM (2010) Neurobiol Aging. doi:10.1016/j.neurobiolaging.2010.04.032

  43. Sullivan EV, Adalsteinsson E, Rohlfing T, Pfefferbaum A (2009) Brain Imaging Behav 3:167

    Article  PubMed  Google Scholar 

  44. Vasudevaraju P, Bharathi TJ, Shamasundar NM, Subba Rao K, Balaraj BM, Ksj R (2010) Indian J Psychiatry 52:140

    Article  PubMed  CAS  Google Scholar 

  45. Kastman EK, Willette AA, Coe CL, Bendlin BB, Kosmatka KJ, McLaren DG, Xu G, Canu E, Field AS, Alexander AL, Voytko ML, Beasley TM, Colman RJ, Weindruch RH, Johnson SC (2010) J Neurosci 30:7940

    Article  PubMed  CAS  Google Scholar 

  46. House MJ, St Pierre TG, Milward EA, Bruce DG, Olynyk JK (2010) Magn Reson Med 63:275

    Article  PubMed  CAS  Google Scholar 

  47. Crichton RR, Ward RJ (2006) Metal-based neurodegeneration. From molecular mechanisms to therapeutic strategies. Wiley, Chichester, p 227

    Google Scholar 

  48. Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A (2003) Trends Mol Med 9:169

    Article  PubMed  CAS  Google Scholar 

  49. Benedetti A, Pmpella A, Fulceri R, Romani A, Comporti M (1986) Toxicol Pathol 14:457

    Article  PubMed  CAS  Google Scholar 

  50. Catala A (2009) Chem Phys Lipids 157:1

    Article  PubMed  CAS  Google Scholar 

  51. Schneider C, Porter NA, Brash AR (2008) J Biol Chem 283:15539

    Article  PubMed  CAS  Google Scholar 

  52. Zarkovic N (2003) Mol Aspects Med 24:281

    Article  PubMed  CAS  Google Scholar 

  53. Zarkovic K (2003) Mol Aspects Med 24:293

    Article  PubMed  CAS  Google Scholar 

  54. Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA (2008) J Biol Chem 283:21837

    Article  PubMed  CAS  Google Scholar 

  55. Berlett BS, Stadtman ER (1997) J Biol Chem 272:20313

    Article  PubMed  CAS  Google Scholar 

  56. Beal MF (2002) Free Radic Biol Med 32:797

    Article  PubMed  CAS  Google Scholar 

  57. Stadtman ER (2006) Free Radic Res 40:1250

    Article  PubMed  CAS  Google Scholar 

  58. Sayre LM, Lin D, Yuan Q, Zhu X, Tang X (2006) Drug Metab Rev 38:651

    Article  PubMed  CAS  Google Scholar 

  59. Oe T, Arora JS, Lee SH, Blair IA (2003) J Biol Chem 27:42098

    Article  CAS  Google Scholar 

  60. Zhang WH, Liu J, Xu G, Yuan Q, Sayre LM (2003) Chem Res Toxicol 16:512

    Article  PubMed  CAS  Google Scholar 

  61. Bush AL, Tanzi RE (2002) Proc Natl Acad Sci USA 99:97317

    Google Scholar 

  62. Honda K, Casadesus G, Peterson RB, Perry G, Smith MA (2004) Ann NY Acad Sci 1012:179

    Article  PubMed  CAS  Google Scholar 

  63. Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM, Hattier T, Harris PL, Siedlak SL, Fujioka H, Liu Q, Moreira PI, Miller FP, Nunomura A, Shimohama S, Perry G (2005) J Biol Chem 280:20978

    Article  PubMed  CAS  Google Scholar 

  64. Sipe JC, Lee P, Beutler E (2002) Dev Neurosci 24:188

    Article  PubMed  CAS  Google Scholar 

  65. Connor JR, Snyder BS, Beard JL, Fine RE, Mufson EJ (1992) J Neurosci Res 31:327

    Article  PubMed  CAS  Google Scholar 

  66. Smith MA, Harris PL, Sayre LM, Perry G (1997) Proc Natl Acad Sci USA 94:9866

    Article  PubMed  CAS  Google Scholar 

  67. Tachida Y, Nakagawa K, Saito T, Saido TC, Honda T, Saito Y, Murayama S, Endo T, Sakaguchi G, Kato A, Kitazume S, Hashimoto Y (2008) J Neurochem 104:1387

    Article  PubMed  CAS  Google Scholar 

  68. Seidah NG, Chrétien M, Day R (1994) Biochimie 76:197

    Article  PubMed  CAS  Google Scholar 

  69. Silvestri L, Pagani A, Camaschella C (2008) Blood 111:924

    Article  PubMed  CAS  Google Scholar 

  70. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY (2006) Nat Genet 38:531

    Article  PubMed  CAS  Google Scholar 

  71. McMahon S, Grondin F, McDonald PP, Richard DE, Dubois CM (2005) J Biol Chem 280:6561

    Article  PubMed  CAS  Google Scholar 

  72. Silvestri L, Camaschella C (2008) J Cell Mol Med 12:1548

    Article  PubMed  CAS  Google Scholar 

  73. Mueller S (2005) Biofactors 24:171

    Article  PubMed  CAS  Google Scholar 

  74. Hwang EM, Kim SK, Sohn JH, Lee JY, Kim Y, Kim YS, Mook-Jung I (2006) Biochem Biophys Res Commun 349:654

    Article  PubMed  CAS  Google Scholar 

  75. Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, Leiter L, McPhee J, Sarang SS, Utsuki T, Greig NH, Lahiri DK, Tanzi RE, Bush Al, Giordano T, Gullans SR (2002) J Biol Chem 277:45518

    Article  PubMed  CAS  Google Scholar 

  76. Duce JA, Tsatsanis A, Cater MA, Janes SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho H-H, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (2010) Cell 142:857

    Article  PubMed  CAS  Google Scholar 

  77. Schapira AH, Olanow CW (2004) JAMA 291:358

    Article  PubMed  CAS  Google Scholar 

  78. Crichton RR (2009) Inorganic biochemistry of iron metabolism. from molecular mechanisms to clinical consequences, 3rd edn. Wiley, Chichester, p 461

    Google Scholar 

  79. Oakley AE, Collingwood JF, Dobson L, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (2007) Neurology 68:1820

    Article  PubMed  CAS  Google Scholar 

  80. Goedert M (2001) Nat Rev Neurosci 2:492

    Article  PubMed  CAS  Google Scholar 

  81. Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B (2002) J Biol Chem 277:16116

    Article  PubMed  CAS  Google Scholar 

  82. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E (1999) Neuroreport 10:717

    Article  PubMed  CAS  Google Scholar 

  83. Münch G, Lüth HJ, Wong A, Arendt T, Hirsch E, Ravid R, Riederer P (2000) J Chem Neuroanat 20:253

    Article  PubMed  Google Scholar 

  84. Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) J Neurosci 20:6048

    PubMed  CAS  Google Scholar 

  85. Sangchot P, Sharma S, Chetsawang B, Porter J, Govitrapong P, Ebadi M (2002) Dev Neurosci 24:143

    Article  PubMed  CAS  Google Scholar 

  86. Takanashi M, Mochizuki H, Yokomizo K, Hattori N, Mori H, Yamamura Y, Mizuno Y (2001) Parkinsonism Relat Disord 7:311

    Article  PubMed  Google Scholar 

  87. Castellani RJ, Siedlak SL, Perry G, Smith MA (2000) Acta Neuropathol 100:111

    Article  PubMed  CAS  Google Scholar 

  88. Arawaka S, Saito Y, Murayama S, Mori H (1998) Neurology 51:887

    Article  PubMed  CAS  Google Scholar 

  89. Kaltschmidt C, Kaltschmidt B, Lannes-Vieira J, Kreutzberg GW, Wekerle H, Baeuerle PA, Gehrmann J (1994) J Neuroimmunol 55:99

    Article  PubMed  CAS  Google Scholar 

  90. Zhang W, Murao K, Zhange X, Matsumoto K, Diah S, Okada M, Miyake K, Kawai N, Tamiya T (2010) BMC Cancer 10:593

    Article  PubMed  CAS  Google Scholar 

  91. Ward RJ, Lallemand F, de Witte P, Crichton RR, Piette J, Tipton K, Hemmings K, Pitard A, Page M, Della Corte L, Taylor D, Dexter DT (2011) Biochem Pharmacol 81:743–751

    Google Scholar 

  92. Ward RJ, Dexter D, Florence A, Aouad F, Hider R, Jenner P, Crichton RR (1995) Biochem Pharmacol 49:1821

    Article  PubMed  CAS  Google Scholar 

  93. Hua Y, Keep RF, Hoff JT, Xi G (2008) Acta Neurochir Suppl 105:3

    Article  PubMed  CAS  Google Scholar 

  94. Selim M (2009) Stroke 40:S90

    Article  PubMed  CAS  Google Scholar 

  95. Shachar DB, Kahana N, Kampel V, Warshawsky A, Youdim MB (2004) Neuropharmacology 46:254

    Article  PubMed  CAS  Google Scholar 

  96. Dexter DT, Statton S, Whitmore C, Freinbichler W, Weinberger P, Tipton KT, Della Corte L, Ward RJ, Crichton RR (2011) J Neural Trans 118:223–231

    Google Scholar 

  97. Crichton RR, Dexter DT, Ward RJ (2008) Coord Chem Rev 252:1189

    Article  CAS  Google Scholar 

  98. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2009) Neurobiol Dis 37:13

    Article  PubMed  CAS  Google Scholar 

  99. Zimmer M, Ebert BL, Neil C, Brenner K, Papaioannou I, Melas A, Tolliday N, Lamb J, Pantopoulos K, Golub T, Iliopoulos O (2008) Mol Cell 32:838

    Article  PubMed  CAS  Google Scholar 

  100. Hentze MW, Kühn LC (1996) Proc Natl Acad Sci USA 93:8175

    Article  PubMed  CAS  Google Scholar 

  101. Cho HH, Cahill CM, Vanderburg CR, Scherzer CR, Wang B, Huang X, Rogers JT (2010) J Biol Chem 285:31217

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Grateful thanks are due to COST D34 for facilitating the interaction between the authors.

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Authors and Affiliations

  1. Institute of Condensed Material and Nanosciences, Université Catholique de Louvain, Place Louis Pasteur 1, 1348, Louvain-la-Neuve, Belgium

    Robert R. Crichton

  2. Department of Cellular and Molecular Neuroscience, Faculty of Medicine, Imperial College London, London, UK

    David T. Dexter & Roberta J. Ward

  3. Biologie du Comportement, Université Catholique de Louvain, Louvain-la-Neuve, Belgium

    Roberta J. Ward

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  1. Robert R. Crichton
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  2. David T. Dexter
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  3. Roberta J. Ward
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Correspondence to Robert R. Crichton .

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Editors and Affiliations

  1. , Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9, Vienna, 1060, Austria

    Wolfgang Linert

  2. Faculty of Chemistry, University of Wroclaw, ul. Fryderyka Joliot Curie 14, Wroclaw, 50-383, Poland

    Henryk Kozlowski

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Crichton, R.R., Dexter, D.T., Ward, R.J. (2012). Brain iron metabolism and its perturbation in neurological diseases. In: Linert, W., Kozlowski, H. (eds) Metal Ions in Neurological Systems. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1001-0_1

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