Skip to main content

Advertisement

SpringerLink
Log in

Brain iron metabolism and its perturbation in neurological diseases

  • Basic Neurosciences, Genetics and Immunology - Review article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Metal ions are of particular importance in brain function, notably iron. A broad overview of iron metabolism and its homeostasis both at the cellular level (involving regulation at the level of mRNA translation) and the systemic level (involving the peptide ‘hormone’ hepcidin) is presented. The mechanisms of iron transport both across the blood–brain barrier and within the brain are then examined. The importance of iron in the developing foetus and in early life is underlined. We then review the growing corpus of evidence that many neurodegenerative diseases (NDs) are the consequence of dysregulation of brain iron homeostasis. This results in the production of reactive oxygen species, generating reactive aldehydes, which, together with further oxidative insults, causes oxidative modification of proteins, manifested by carbonyl formation. These misfolded and damaged proteins overwhelm the ubiquitin/proteasome system, accumulating the characteristic inclusion bodies found in many NDs. The involvement of iron in Alzheimer’s disease and Parkinson’s disease is then examined, with emphasis on recent data linking in particular interactions between iron homeostasis and key disease proteins. We conclude that there is overwhelming evidence for a direct involvement of iron in NDs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Notes

  1. Other proteins with functional IREs in their 5′-UTR include hypoxia-inducible factor 2a (Zimmer et al. 2008), erythroid aminolaevulinate synthase and mitochondrial aconitase (reviewed in Hentze and Kühn 1996) and more recently amyloid precursor protein (Cho et al. 2010).

References

  • Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2009) Structure and function of the blood–brain barrier. Neurobiol Dis 37:13–25

    Article  PubMed  Google Scholar 

  • Altamura S, Muckenthaler MU (2009) Iron toxicity in diseases of ageing: Alzheimer’s Disease, Parkinson’s Disease and Atherosclerosis. J Alzheimers Dis 16:879–895

    PubMed  Google Scholar 

  • Arawaka S, Saito Y, Murayama S, Mori H (1998) Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein. Neurology 51:887–889

    PubMed  CAS  Google Scholar 

  • 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) Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38:531–539

    Article  PubMed  CAS  Google Scholar 

  • Beal MF (2002) Oxidatively modified proteins in aging and disease. Free Radic Biol Med 32:797–803

    Article  PubMed  CAS  Google Scholar 

  • Beard JL (2008) Why iron deficiency is important in infant development. J Nutr 138:2534–2536

    PubMed  CAS  Google Scholar 

  • Beard JL, Wiesinger JA, Connor JR (2003a) Pre- and postweaning iron deficiency alters myelination in Sprague–Dawley rats. Dev Neurosci 25:308–315

    Article  PubMed  CAS  Google Scholar 

  • Beard J, Erikson KM, Jones BC (2003b) Neonatal iron deficiency results in irreversible changes in dopamine function in rats. J Nutr 133:1174–1179

    PubMed  CAS  Google Scholar 

  • Berlett BS, Stadtman ER (1997) Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 272:20313–20316

    Article  PubMed  CAS  Google Scholar 

  • Bradbury MWB (1997) Transport of iron in the blood–brain–cerebrospinal fluid system. J Neurochem 67:443–454

    Google Scholar 

  • Burdette SC, Lippard SJ (2003) Meeting of the minds: metalloneurochemistry. Proc Natl Acad Sci USA 100:3605–3610

    Article  PubMed  CAS  Google Scholar 

  • Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 66:1198–1207

    Article  PubMed  CAS  Google Scholar 

  • Burhans MS, Dailey C, Beard Z, Wiesinger J, Murray-Kolb L, Jones BC, Beard JL (2005) Iron deficiency: differential effects on monoamine transporters. Nutr Neurosci 8:31–38

    Article  PubMed  CAS  Google Scholar 

  • Bush AL, Tanzi RE (2002) The galvanization of beta-amyloid in Alzheimer’s disease. Proc Natl Acad Sci USA 99:97317–97319

    Google Scholar 

  • Castellani RJ, Siedlak SL, Perry G, Smith MA (2000) Sequestration of iron by Lewy bodies in Parkinson’s disease. Acta Neuropathol 100:111–114

    Article  PubMed  CAS  Google Scholar 

  • Catala A (2009) Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids 157:1–11

    Article  PubMed  CAS  Google Scholar 

  • Cho HH, Cahill CM, Vanderburg CR et al (2010) Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1. J Biol Chem. doi:10.1074/jbc.M110.149161

  • Connor JR, Snyder BS, Beard JL, Fine RE, Mufson EJ (1992) Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer’s disease. J Neurosci Res 31:327–335

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Crichton RR (2009) Inorganic biochemistry of iron metabolism from molecular mechanisms to clinical consequences, 3rd edn. John Wiley and Sons, Chichester, pp 461

  • Crichton RR, Ward RJ (2006) Metal-based neurodegeneration. From molecular mechanisms to therapeutic strategies John Wiley and Sons, pp 227

  • Crichton RR, Dexter DT, Ward RJ (2008) Metal based neurodegenerative diseases—from molecular mechanisms to therapeutic strategies. Coord Chem Rev 252:1189–1199

    Article  CAS  Google Scholar 

  • Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A (2003) Protein carbonylation in human disease. Trends Mol Med 9:169–176

    Article  PubMed  CAS  Google Scholar 

  • Dallman PR, Beutler E, Finch CA (1978) Effects of iron deficiency exclusive of anaemia. Br J Haematol 40:179–184

    Article  PubMed  CAS  Google Scholar 

  • Dallman PR, Siimes MA, Stekel A (1980) Iron deficiency in infancy and childhood. Am J Clin Nutr 33:86–118

    PubMed  CAS  Google Scholar 

  • De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, Kaplan J (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI–ceruloplasmin. EMBO J 26:2823–2831

    Article  PubMed  Google Scholar 

  • Fischer J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA, Connor JR (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293:C641–C649

    Article  Google Scholar 

  • Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501

    Article  PubMed  CAS  Google Scholar 

  • Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B (2002) Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. J Biol Chem 277:16116–16123

    Article  PubMed  CAS  Google Scholar 

  • Götz ME, Double K, Gerlach M, Youdim MB, Riederer P (2004) The relevance of iron in the pathogenesis of Parkinson’s disease. Ann NY Acad Sci 1012:193–208

    Article  PubMed  Google Scholar 

  • Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA (2008) Oxidative stress and covalent modification of proteins with bioreactive aldehydes. J Biol Chem 283:21837–21841

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E (1999) Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport 10:717–721

    Article  PubMed  CAS  Google Scholar 

  • Hentze MW, Kühn LC (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Ssci USA 93:8175–8182

    Article  CAS  Google Scholar 

  • Honda K, Casadesus G, Peterson RB, Perry G, Smith MA (2004) Oxidative stress and redox-active iron in Alzheimer’s disease. Ann NY Acad Sci 1012:179–182

    Article  PubMed  CAS  Google Scholar 

  • 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) Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem 280:20978–20986

    Article  PubMed  CAS  Google Scholar 

  • Hwang EM, Kim SK, Sohn JH, Lee JY, Kim Y, Kim YS, Mook-Jung I (2006) Furin is an endogenous regulator of alpha-secretase associated APP processing. Biochem Biophys Res Commun 349:654–659

    Article  PubMed  CAS  Google Scholar 

  • Jeong SY, David S (2003) Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 278:27144–27148

    Article  PubMed  CAS  Google Scholar 

  • Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T (2006) Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev 64:S34–S43

    Article  PubMed  Google Scholar 

  • McMahon S, Grondin F, McDonald PP, Richard DE, Dubois CM (2005) Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. J Biol Chem 280:6561–6569

    Article  PubMed  CAS  Google Scholar 

  • Moos T, Morgan EH (2002) A morphological study of the developmentally regulated transport of iron into the brain. Dev Neurosci 24:99–105

    Article  PubMed  CAS  Google Scholar 

  • Moos T, Morgan EH (2004) The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. J Neurochem 88:233–245

    Article  PubMed  CAS  Google Scholar 

  • Moos T, Rosengren Nielsen T (2006) Ferroportin in the postnatal rat brain: implications for axonal transport and neuronal export of iron. Semin Pediatr Neurol 13:149–157

    Article  PubMed  Google Scholar 

  • Moos T, Oates PS, Morgan EH (1998) Expression of the neuronal transferrin receptor is age dependent and susceptible to iron deficiency. J Comp Neurol 31:420–439

    Article  Google Scholar 

  • Moos T, Skjoerringe T, Gosk S, Morgan EH (2006) Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J Neurochem 98:1946–1958

    Article  PubMed  CAS  Google Scholar 

  • Moos T, Rosengren Nielsen T, Skjørringe T, Morgan EH (2007) Iron trafficking inside the brain. J Neurochem 103:1730–1740

    Article  PubMed  CAS  Google Scholar 

  • Morgan EH (1977) Iron exchange between transferrin molecules mediated by phosphate compounds and other cell metabolites. Biochim Biophys Acta 499:169–177

    PubMed  CAS  Google Scholar 

  • Morgan EH (1979) Studies on the mechanism of iron release from transferrin. Biochim Biophys Acta 580:312–326

    PubMed  CAS  Google Scholar 

  • Mueller S (2005) Iron regulatory protein 1 as a sensor of reactive oxygen species. Biofactors 24:171–181

    Article  PubMed  CAS  Google Scholar 

  • Münch G, Lüth HJ, Wong A, Arendt T, Hirsch E, Ravid R, Riederer P (2000) Crosslinking of alpha-synuclein by advanced glycation endproducts—an early pathophysiological step in Lewy body formation? J Chem Neuroanat 20:253–257

    Article  PubMed  Google Scholar 

  • Oakley AE, Collingwood JF, Dobson L et al (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68:1820–1825

    Article  PubMed  CAS  Google Scholar 

  • Oe T, Arora JS, Lee SH, Blair IA (2003) A novel lipid hydroperoxide-derived cyclic covalent modification to histone H4. J Biol Chem 27:42098–42105

    Article  Google Scholar 

  • Ohgami RS, Campagne DR, McDonald A, Fleming MD (2006) The Steap proteins are metalloreductases. Blood 108:1388–1394

    Article  PubMed  CAS  Google Scholar 

  • Ortiz E, Pasquini JM, Thompson K, Felt B, Butkus G, Beard J, Connor JR (2004) Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J Neurosci Res 77:681–689

    Article  PubMed  CAS  Google Scholar 

  • Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054

    PubMed  CAS  Google Scholar 

  • Rao R, Georgieff MK (2007) Iron in fetal, neonatal nutrition. Semin Fetal Neonatal Med 12:54–63

    Article  PubMed  Google Scholar 

  • Rao R, Tkac I, Townsend EL, Gruetter R, Georgieff MK (2003) Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus. J Nutr 133:3215–3221

    PubMed  CAS  Google Scholar 

  • Rao R, Tkac I, Townsend EL, Ennis K, Gruetter R, Georgieff MK (2007) Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia-ischemia. J Cereb Blood Flow Metab 27:872

    Article  Google Scholar 

  • 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, Al Bush, Giordano T, Gullans SR (2002) An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 277:45518–45528

    Article  PubMed  CAS  Google Scholar 

  • Rouault TA, Cooperman S (2006) Brain iron metabolism. Semin Pediatr Neurol 13:142–148

    Article  PubMed  Google Scholar 

  • Sangchot P, Sharma S, Chetsawang B, Porter J, Govitrapong P, Ebadi M (2002) Deferoxamine attenuates iron-induced oxidative stress and prevents mitochondrial aggregation and alpha-synuclein translocation in SK–N–SH cells in culture. Dev Neurosci 24:143–153

    Article  PubMed  CAS  Google Scholar 

  • Sayre LM, Lin D, Yuan Q, Zhu X, Tang X (2006) Protein adducts generated from products of lipid oxidation: focus on HNE and ONE. Drug Metab Rev 38:651–675

    Article  PubMed  CAS  Google Scholar 

  • Schapira AH, Olanow CW (2004) Neuroprotection in Parkinson’s disease: mysteries, myths, and misconceptions. JAMA 291:358–364

    Article  PubMed  CAS  Google Scholar 

  • Schneider C, Porter NA, Brash AR (2008) Routes to 4-hydroxynonenol: fundamental Issues in the mechanism of lipid peroxidation. J Biol Chem 283:15539–15543

    Article  PubMed  CAS  Google Scholar 

  • Seidah NG, Chrétien M, Day R (1994) The family of subtilisin/kexin like pro-protein and pro-hormone convertases: divergent or shared functions. Biochimie 76:197–209

    Article  PubMed  CAS  Google Scholar 

  • Silvestri L, Camaschella C (2008) A potential pathogenetic role of iron in Alzheimer’s disease. J Cell Mol Med 12:1548–1550

    Article  PubMed  CAS  Google Scholar 

  • Silvestri L, Pagani A, Camaschella C (2008) Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood 111:924–931

    Article  PubMed  CAS  Google Scholar 

  • Sipe JC, Lee P, Beutler E (2002) Brain iron metabolism and neurodegenerative disorders. Dev Neurosci 24:188–196

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, Harris PL, Sayre LM, Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 94:9866–9868

    Article  PubMed  CAS  Google Scholar 

  • Stadtman ER (2006) Protein oxidation, ageing. Free Radic Res 40:1250–1258

    Article  PubMed  CAS  Google Scholar 

  • 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) Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. J Neurochem 104:1387–1393

    Article  PubMed  CAS  Google Scholar 

  • Takanashi M, Mochizuki H, Yokomizo K, Hattori N, Mori H, Yamamura Y, Mizuno Y (2001) Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP). Parkinsonism Relat Disord 7:311–314

    Article  PubMed  Google Scholar 

  • Ward KL, Tkac I, Jing Y, Felt B, Beard J, Connor J, Schallert T, Georgieff MK, Rao R (2007) Gestational and lactational iron deficiency alters the developing striatal metabolome and associated behaviors in young rats. J Nutr 137:1043–1049

    PubMed  CAS  Google Scholar 

  • Woods HF, Youdim MB, Boullin D, Callender S (1976) Monoamine metabolism and platelet function in iron-deficiency anaemia. Ciba Found Symp 51:227–248

    PubMed  Google Scholar 

  • Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004) Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier. Brain Res 1001:108–117

    Article  PubMed  CAS  Google Scholar 

  • Zarkovic N (2003a) 4-Hydroxynonenal as a bioactive marker of pathophysiological processes. Mol Aspects Med 24:281–291

    Article  PubMed  CAS  Google Scholar 

  • Zarkovic K (2003b) 4-Hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 24:293–303

    Article  PubMed  CAS  Google Scholar 

  • Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, Giaveri G, Arosio P et al (2004a) The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci USA 101:9843–9848

    Article  PubMed  CAS  Google Scholar 

  • Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004b) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873

    Article  PubMed  CAS  Google Scholar 

  • Zhang WH, Liu J, Xu G, Yuan Q, Sayre LM (2003) Model studies on protein side chain modification by 4-oxo-2-nonenal. Chem Res Toxicol 16:512–523

    Article  PubMed  CAS  Google Scholar 

  • Zimmer M, Ebert BL, Neil C et al (2008) Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol Cell 32:838–848

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

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, Hammersmith Hospital Campus, Du Cane Road, London, W12 ONN, UK

    David T. Dexter

  3. Earth and Life Institut, Université Catholique de Louvain, Place Croix du Sud, 1348, Louvain-la-Neuve, Belgium

    Roberta J. Ward

Authors
  1. Robert R. Crichton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David T. Dexter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberta J. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert R. Crichton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Crichton, R.R., Dexter, D.T. & Ward, R.J. Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm 118, 301–314 (2011). https://doi.org/10.1007/s00702-010-0470-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-010-0470-z

Keywords

Search

Navigation