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Brain Iron Metabolism and CNS Diseases

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Brain Iron Metabolism and CNS Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1173))

Abstract

Iron is the most abundant trace element in the human body. It is well known that iron is an important component of hemoglobin involved in the transport of oxygen. As a component of various enzymes, it participates in the tricarboxylic acid cycle and oxidative phosphorylation. Iron in the nervous system is also involved in the metabolism of catecholamine neurotransmitters and is involved in the formation of myelin. Therefore, iron metabolism needs to be strictly regulated. Previous studies have shown that iron deficiency in the brain during infants and young children causes mental retardation, such as delayed development of language and body balance, and psychomotor disorders. However, if the iron is excessively deposited in the aged brain, it is closely related to the occurrence of various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia. Therefore, it is important to fully study and understand the mechanism of brain iron metabolism and its regulation. On this basis, exploring the relationship between brain iron regulation and the occurrence of nervous system diseases and discovering new therapeutic targets related to iron metabolism have important significance for breaking through the limitation of prevention and treatment of nervous system diseases. This review discusses the complete research history of iron and its significant role in the pathogenesis of the central nervous system (CNS) diseases.

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References

  1. Andersen HH, Johnsen KB, Moos T (2014) Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration. Cell Mol Life Sci 71:1607–1622

    Article  CAS  Google Scholar 

  2. Appleton TC, Morgan E, Baker E (1971) A morphological study of transferrin uptake by reticulocytes. In: Trávníèek T, Neuwirt J (eds) The regulation of erythropoiesis and haemoglobin synthesis. Universita karlova, prague, pp 310

    Google Scholar 

  3. Birkmayer W, Hornykiewicz O (1961) The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia. Wien Klin Wochenschr 73:787–788

    CAS  PubMed  Google Scholar 

  4. Busacchi V (1958) Vincenzo Menghini and the discovery of iron in the blood. Bull Sci Med (bologna) 130:202–205

    Google Scholar 

  5. Charcot JM (1872) De la paralysie agitante. In: Oeuvres Complètes (t1) Leçons sur les maladies du système nerveux, pp 155–188. Delahaye A, Paris: In: English: Charcot JM. 1877. On Parkinson’s disease. In Lectures on diseases of the nervous system delivered at the Salpêtrière (trans: Sigerson G). New Sydenham Society, London, pp 129–156

    Google Scholar 

  6. Chen H, Attieh ZK, Syed BA, Kuo YM, Stevens V, Fuqua BK, Andersen HS, Naylor CE, Evans RW, Gambling L et al (2010) Identification of zyklopen, a new member of the vertebrate multicopper ferroxidase family, and characterization in rodents and human cells. J Nutr 140:1728–1735

    Article  CAS  Google Scholar 

  7. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP et al (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28:350–354

    Article  CAS  Google Scholar 

  8. Conrad ME Jr, Crosby WH (1963) Intestinal mucosal mechanisms controlling iron absorption. Blood 22:406–415

    CAS  PubMed  Google Scholar 

  9. Conrad S, Genth H, Hofmann F, Just I, Skutella T (2007) Neogenin-RGMa signaling at the growth cone is bone morphogenetic protein-independent and involves RHoA, ROCKk, and PKC. J Biol Chem 282:16423–16433

    Article  CAS  Google Scholar 

  10. Deane R, Zheng W, Zlokovic BV (2004) Brain capillary endothelium and choroid plexus epithelium regulate transport of transferrin-bound and free iron into the rat brain. J Neurochem 88:813–820

    Article  CAS  Google Scholar 

  11. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781

    Article  CAS  Google Scholar 

  12. Drysdale JW, Munro HN (1965) Failure of actinomycin D to prevent induction of liver apoferritin after iron administration. Biochim Biophys Acta 103:185–188

    Article  CAS  Google Scholar 

  13. Ehringer H, Hornykiewicz O (1960) Verteilung von noradrenalin and dopamin im gehirn des menschen und ihr verhalten bei erkrankungen des extrapyramidalen systems. Klin Wschr 38:1126–1239

    Article  Google Scholar 

  14. Fenton HJH (1876) On a new reaction or tartaric acid. Chemical News 33:190

    Google Scholar 

  15. Fenton HJH (1893) The oxidation of tartaric acid in presence of iron. Chem Soc Proc 9:113

    Google Scholar 

  16. Fineberg RA, Greenberg DM (1955) Ferritin biosynthesis II. Acceleration of synthesis by the administration of iron. J Biol Chem 214:97–106

    CAS  PubMed  Google Scholar 

  17. Finch CA (1959) Body iron exchange in man. J Clin Invest 38:392–396

    Article  CAS  Google Scholar 

  18. Fontés G, Thivolle I (1925) Sur la teneur du sérum en fer non hémoglobinique et sur sa diminution au cours de l’anémie expérimentale. Compt Rend Soc Biol 96:687

    Google Scholar 

  19. Gowers WR (1899) Paralysis agitans. In: Allbutt A, Rolleston T (eds) A system of medicine. Macmillan, London, pp 156–178

    Google Scholar 

  20. Guo B, Phillips JD, Yu Y, Leibold EA (1995) Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem 270:21645–21651

    Article  CAS  Google Scholar 

  21. Hahn PF, Bale WF, Ross JF, Balfour WM, Whipple GH (1943) Radioactive iron absorption by gastrointestinal tract: influence of anemia, anoxia, and antecedent feeding distribution in growing dogs. J Exp Med 78:169–188

    Article  CAS  Google Scholar 

  22. Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL et al (2004) Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci U S A 101:13850–13855

    Article  CAS  Google Scholar 

  23. Halliwell B, Gutteridge JM (1984) Role of iron in oxygen radical reactions. Methods Enzymol 105:47–56

    Article  CAS  Google Scholar 

  24. Hentz MW, Kuhn LC (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci U S A 93:8175–8182

    Article  Google Scholar 

  25. Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Two to tango: regulation of mammalian iron metabolism. Cell 142:24–38

    Article  CAS  Google Scholar 

  26. Holmberg CG, Laurell CB (1945) Studies on the capacity of serum to bind iron—a contribution to our knowledge of the regulation mechanism of serum iron. Acta Physiol Scand 10:307

    Article  CAS  Google Scholar 

  27. Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I, Macharouthu A, O’Brien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R, Knapp M, Ballard C, Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P (2012) Donepezil and meantime for moderate-to-severe Alzheimer’s disease. N Engl J Med 366:893–903

    Article  CAS  Google Scholar 

  28. Hornykiewicz O (2002) Dopamine miracle: from brain homogenate to dopamine replacement. Mov Disord 17:501–508

    Article  Google Scholar 

  29. Holtz P, Heise R, Lüdtke K (1938) Fermentative degradation of l-dioxyphenylalanine (dopa) by kidney. Naunyn-Schmiedeberg’s Arch. Pharmacol 191:87–118

    Article  CAS  Google Scholar 

  30. Jandl JH, Katz JH (1963) The plasma-to-cell cycle of transferrin. J Clin Invest 42:314–326

    Article  CAS  Google Scholar 

  31. Kasarskis EJ, Tandon L, Lovell MA, Ehmann WD (1995) Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: a preliminary study. J Neurol Sci 130:203–208

    Article  CAS  Google Scholar 

  32. Ke Y, Qian ZM (2007) Brain iron metabolism: neurobiology and neurochemistry. Prog Neurobiol 83:149–173

    Article  CAS  Google Scholar 

  33. Leibold EA, Munro HN (1988) Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5′ untranslated region of ferritin heavy- and light-subunit mRNAs. Proc Natl Acad Sci U S A. 85:2171–2175

    Article  CAS  Google Scholar 

  34. Lecanu LR, l’hématosine de (1830) O matière colorante du sang. Ann Chim 45:5–27

    Google Scholar 

  35. Lecanu LR (1831) Nouvelle recherches sur le sang. Ann Chim 48:308–327

    Google Scholar 

  36. Li X, Jankovic J, Le W (2011) Iron chelation and neuroprotection in NDs. J Neural Trans 118:473–477

    Article  CAS  Google Scholar 

  37. Manyam BV (1990) Paralysis agitans and levodopa in “Ayurveda”: ancient Indian medical treatise. Mov Disord 5(1):47–48

    Article  CAS  Google Scholar 

  38. Malecki EA, Devenyi AG, Beard JL, Connor JR (1999) Existing and emerging mechanisms for transport of iron and manganese to the brain. J Neurosci Res 56:113–122

    CAS  PubMed  Google Scholar 

  39. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309

    Article  CAS  Google Scholar 

  40. McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, BarlowD Bomford A (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291:1755–1759

    Article  CAS  Google Scholar 

  41. Mayajima H (2003) Aceruloplasminemia an iron metabolic disorder. Neuropathology 23:345–350

    Article  Google Scholar 

  42. Monarde N (1925) Joyful newes out of the newe founde worlde. New York

    Google Scholar 

  43. Morgan EH, Appleton TC (1969) Autoradiographic localization of 125-I-labelled transferrin in rabbit reticulocytes. Nature 223:1371–1372

    Article  CAS  Google Scholar 

  44. Mccance RA, Widdowson EM (1938) The absorption and excretion of iron following oral and intravenous administration. J Physiol 94:148–154

    Article  CAS  Google Scholar 

  45. Nicolas G, Bennoun M, Devaux I et al (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A. 98(15):8780–8785

    Article  CAS  Google Scholar 

  46. Oshiro S, Kawahara M, Kuroda Y, Zhang C, Cai Y, Kitajima S, Shirao M (2000) Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells. Biochim Biophys Acta 1502:405–414

    Article  CAS  Google Scholar 

  47. Owen D, Kühn LC (1987) Noncoding 3′ sequences of the transfer in receptor gene are required for mRNA regulation by iron. EMBO J 6:1287–1293

    Article  CAS  Google Scholar 

  48. Parkinson J (1817) An essay on the shaking palsy. Whittingham and Rowland for Sherwood, Needly and Jones, London

    Google Scholar 

  49. Pollycove M, Mortimer R (1961) The quantitative determination of iron kinetics and hemoglobin synthesis in human subjects. J Clin Invest 40:753–782

    Article  CAS  Google Scholar 

  50. Qian ZM, Chang YZ, Zhu L, Yang L, Du JR, Ho KP et al (2007) Development and iron-dependent expression of hephaestin in different brain regions of rats. J Cell Biochem 102:1225–1233

    Article  CAS  Google Scholar 

  51. Rouault TA (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2:406–414

    Article  CAS  Google Scholar 

  52. Schade AL, Caroline I (1944) Raw hen egg white and the role of iron in growth inhibition of Shigella dysenteriae, Staphylococcus aureus, Escherichia coli and Saccharomyces cerevisiae. Science 100:14–15

    Article  CAS  Google Scholar 

  53. Santa-Maria I, Hernández F, Del Rio J, Moreno FJ, Avila J (2007) Tramiprosate, a drug of potential interest for the treatment of Alzheimer’s disease, promotes an abnormal aggregation of tau. Mol Neurodegener 6:17

    Article  Google Scholar 

  54. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I (2004) Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial Memantine Study Group. JAMA 291(3):317–324

    Article  CAS  Google Scholar 

  55. Troadec MB, Warner D, Wallace J et al (2011) Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. Blood 117(20):5494–5502

    Article  CAS  Google Scholar 

  56. Vanotti A, Delachaux A (1949) iron metabolism and its clinical significance. Grune & Stratton, New York

    Google Scholar 

  57. Vivot RM, Goitia B, Usach V, Setton-Avruj PC (2013) DMT1 as a candidate for non-transferrin-bound iron uptake in the peripheral nervous system. BioFactors 39:476–484

    Article  CAS  Google Scholar 

  58. Vulpe CD, Kuo YM, Murphy TL, CowleyL Askwith C, Libina N, Gitschier J, Anderson GJ (1999) Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21:195–199

    Article  CAS  Google Scholar 

  59. Wächtershäuser G (1990) Evolution of the first metabolic cycles. Proc Natl Acad Sci U S A 87:200–204

    Article  Google Scholar 

  60. Wächtershäuser G (2000) Origin of life. Life as we don’t know it. Science 289:1307–1308

    Article  Google Scholar 

  61. Wang SM, Fu LJ, Duan XL, Crooks DR, Yu P, Qian ZM, Di XJ, Li J, Rouault TA, Chang YZ (2010) Role of hepcidin in murine brain iron metabolism. Cell Mol Life Sci 67(1):123–133

    Article  CAS  Google Scholar 

  62. You LH, Yan CZ, Zheng BJ, Ci YZ, Chang SY, Yu P, Gao GF, Li HY, Dong TY, Chang YZ (2017) Astrocyte hepcidin is a key factor in LPS-induced neuronal apoptosis. Cell Death Dis 8(3):e2676

    Article  CAS  Google Scholar 

  63. Zahringer J, Baliga BS, Munro HN (1976) Novel mechanism for translational control in regulation of ferritin synthesis by iron. Proc Natl Acad Sci USA 73:857–861

    Article  CAS  Google Scholar 

  64. Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A et al (2011) Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord 26:1756–1759

    Article  Google Scholar 

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Thirupathi, A., Chang, YZ. (2019). Brain Iron Metabolism and CNS Diseases. In: Chang, YZ. (eds) Brain Iron Metabolism and CNS Diseases. Advances in Experimental Medicine and Biology, vol 1173. Springer, Singapore. https://doi.org/10.1007/978-981-13-9589-5_1

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