Pediatric Neurology
Volume 25, Issue 2 , Pages 118-129 , August 2001

Iron and iron management proteins in neurobiology

  • James R Connor, PhD

      Affiliations

    • Department of Neuroscience and Anatomy, Penn State University College of Medicine; M.S. Hershey Medical Center; Hershey, Pennsylvania, USA
    • Corresponding Author InformationCommunications should be addressed to: Dr. Connor, G.M. Leader Family Laboratory for Alzheimer’s Disease Research; Professor and Vice-Chair; Department of Neuroscience & Anatomy (H109); Penn State University College of Medicine; Hershey, PA 17033
  • ,
  • Sharon L Menzies, BA

      Affiliations

    • Department of Neuroscience and Anatomy, Penn State University College of Medicine; M.S. Hershey Medical Center; Hershey, Pennsylvania, USA
  • ,
  • Joseph R Burdo, BA

      Affiliations

    • Department of Neuroscience and Anatomy, Penn State University College of Medicine; M.S. Hershey Medical Center; Hershey, Pennsylvania, USA
  • ,
  • Philip J Boyer, MD, PhD

      Affiliations

    • Department of Pathology; Penn State University College of Medicine; M.S. Hershey Medical Center; Hershey, Pennsylvania, USA

Received 3 January 2001 ,Accepted 30 April 2001.

References 

  1. Beard JL, Dawson H, Piñero DJ. Iron metabolism (A comprehensive review). Nutr Rev. 1996;54:295–317
  2. Pollitt E. Iron deficiency and educational deficiency. Nutr Rev. 1997;55:133–141
  3. Beard JL, Connor JR, Jones BC. Iron in the brain. Nutr Rev. 1993;51:157–170
  4. Chen Q, Beard JL, Jones BC. Abnormal brain monoamine metabolism in iron deficiency anemia. J Nutr Biochem. 1995;6:486–493
  5. In:  Connor JR editors. Metals and oxidative damage in neurological disorders. New York: Plenum Press; 1997;
  6. Pinero DJ, Connor JR. Iron in the brain (An important contributor in normal and diseased states). Neuroscientist. 2000;6:435–453
  7. Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta. 1998;1366:211–223
  8. Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination. Glia. 1996;17:83–93
  9. Taneja V, Mishra KP, Agarwal KN. Effect of maternal iron deficiency on GABA shunt pathway of developing rat brain. Indian J Exp Biol. 1990;28:466–469
  10. Shinobu LA, Beal MF. The role of oxidative processes and metal ions in aging and Alzheimer Disease. In:  Connor JR editors. Metals and oxidative damage in neurological disorders. New York: Plenum Press; 1997;p. 237–276
  11. Puccio H, Koenig M. Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum Mol Genet. 2000;9:887–892
  12. Hilditch-Maguire P, Tretel F, Passani LA, Auerbach A, Persichetti F, MacDonald ME. Huntingtin (an iron-regulated protein essential for normal nuclear and perinuclear organelles). Hum Mol Genet. 2000;9:2789–2797
  13. Connor JR, Menzies SL, St. Martin SM, Mufson EJ. A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains. J Neurosci Res. 1992;31:75–83
  14. Mantyh PW, Ghilardi JR, Rogers S, DeMaster E, Allen CJ, Stimson ER, et al. Aluminum, iron and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J Neurochem. 1993;61:1171–1174
  15. Rogers JT, Leiter L, McPhee J, Zhan SS, Cahill C, Potter H, et al. Translational regulation of the amyloid precursor protein mRNA by interleukin-1. J Biol Chem. 1999;274:6421–6431
  16. Reiderer P, Sofic E, Rausch W-D, Schmidt B, Reynolds GP, Jellinger K. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 1989;52:515–520
  17. Koeppen . Pediatr Neurol. 2001;24:000–000
  18. Connor JR, Snyder BS, Beard JL, Fine RE, Mufson EJ. Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer’s disease. J Neurosci Res. 1992;31:327–335
  19. Bartzokis G, Beckson M, Hance DB, Marx P, Foster JA, Marder SR. MR evaluation of age-related increase of brain iron in young adult and older normal males. Magn Reson Imaging. 1997;15:29–35
  20. Connor JR, Pavlick G, Karli D, Menzies SL, Palmer C. A histochemical study of iron-positive cells in the developing rat brain. J Comp Neurol. 1995;355:111–123
  21. Aoki S, Okada Y, et al.  Normal deposition of brain iron in childhood and adolescence (MRI imaging at 1.5T). Radiology. 1989;172:381–385
  22. Connor JR. Iron acquisition and expression of iron regulatory proteins in the developing brain (Manipulation by ethanol exposure, dietary deficiency and cellular dysfunction). Dev Neurosci. 1994;6:233–247
  23. Earley CJ, Allen RP, Beard JL, Connor JR. Insight into the pathophysiology of restless legs syndrome. J Neurosci Res. 2000;62:623–628
  24. Walters AS, Mandelbaum DE, Lewin DS, Kugler S, England SJ, Miller M. Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group. Pediatr Neurol. 2000;22:182–186
  25. Roskams AJ, Connor JR. Iron, transferrin, and ferritin in the rat brain during development and aging. J Neurochem. 1994;63:709–716
  26. Miller MW, Roskams AJI, Connor JR. Iron regulation in the developing brain (Effect of in utero ethanol exposure). J Neurochem. 1995;65:373–380
  27. Dallman PR, Siimes MA, Manies EC. Brain iron (Persistent deficiency following short term iron deprivation the young rat). Br J Haematol. 1975;31:209–215
  28. Dallman PR, Spirito RA. Brain iron in the rat (Extremely slow turnover in normal rats may explain the long lasting effects of early iron deficiency). J Nutr. 1977;107:1075–1081
  29. Weinberg J, Dallman PR, Levine S. Iron deficiency during development in the rat (Behavioral and physiological consequences). Pharmacol Biochem Behav. 1980;12:493–502
  30. Weinberg J, Bert LP, Levine S, Dallman PR. Long term effects of early iron deficiency on consummatory behavior in the rat. Pharmacol Biochem Behav. 1981;14:447–453
  31. Pinero DJ, Li NQ, Connor JR, Beard JL. Variations in dietary iron alter brain iron metabolism in developing rats. J Nutr. 2000;130:254–263
  32. Erikson KM, Pinero DJ, Connor JR, Beard JL. Regional brain, iron, ferritin, and transferrin concentrations during iron deficiency and iron repletion in developing rats. J Nutr. 1997;127:2030–2038
  33. Moos T, Trinder D, Morgan EH. Cellular Distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and β2-microglobulin deficient mouse brain. Cell Mol Biol. 2000;46:549–562
  34. Nielsen JE, Jensen LN, Krabbe K. Hereditary hemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome. J Neurol Neurosurg Psychiatry 1995;59:3 318–21.
  35. Berg D, Hoggenmüller U, Hofmann E, et al.  The basal ganglia in haemochromatosis. Neuroradiology. 2000;42:9–13
  36. Connor JR, Milward EA, Moalem S, et al. Is hemochromatosis a risk factor for Alzheimer disease? J Alzheimer’s Dis (In press).
  37. Nguyen-Legros J, Bizot J, Bolesse J, Policani J. Noir de diaminobenzidine (une nouvelle methode histochemique de revelation du fer exogene). Histochemistry. 1966;66:239–244
  38. Adams JC. Heavy metal intensification of DAB-based HRP reaction product. J Histochem Cytochem. 1981;29:775
  39. Rajan KS, Colburn RW, Davis JM. Distribution of metal ions in the subcellular fractions of several rat brain areas. Life Sci. 1976;18:423–431
  40. Francois CJ, Nguyen-Legros J, Pencheron G. Topographical and cytological localization of iron in rat and monkey brain. Brain Res. 1981;215:317–322
  41. Levine SM. Oligodendrocytes and myelin sheaths in normal, quaking and shiverer brains are enriched in iron. J Neurosci Res. 1991;29:413–419
  42. Connor JR, Menzies SL. Cellular management of iron in the brain. J Neurol Sci. 1995;134(Suppl):33–44
  43. Burdo JR, Martin J, Menzies SL, et al.  Cellular distribution of iron in the brain of the Belgrade rat. Neuroscience. 1999;93:1189–1196
  44. Lin HH, Connor JR. The development of transferrin and the transferrin receptor in relation to glial markers in the normal myelin deficient rat optic nerve. Dev Brain Res. 1989;49:281–293
  45. Skoff RP, Toland D, Nast E. Pattern of myelination and distribution of neuroglial cells along the developing optic system of the rat and rabbit. J Comp Neurol. 1980;191:237–252
  46. Bowern N, Ramshaw IA, Clark IA, Doherty PC. Inhibition of autoimmune neuropathological process by treatment with an iron chelating agent. J Exp Med. 1984;160:1532–1543
  47. Leeden RW, Chakraborty G. Cytokines, signal transduction, and inflammatory demyelination (review and hypothesis). Neurochem Res. 1998;23:277–289
  48. Smirnov IM, Bailey K, Flowers CH, Garrigues NW, Wesselius LJ. Effects of TNF-α and IL-1β on iron metabolism by A459 cells and influence on cytotoxicity. Am J Physiol. 1999;277:L257–L263
  49. Connor JR, Menzies SL. Altered cellular distribution of iron in the CNS of myelin deficient rats. Neuroscience. 1990;34:265–271
  50. Cheepsunthorn P, Palmer C, Menzies S, Roberts RL, Connor JR. Hypoxic/ischemic insult alters ferritin expression and myelination in neonatal rat brains. J Comp Neurol. 2001;431:382–396
  51. Sastry A, Arendash GW. Time dependent changes in iron levels and associated neuronal loss within the substantia nigra following lesions within the neostriatum/globus pallidus complex. Neuroscience. 1995;67:649–666
  52. Gelman BB, Rodriguz-Wolf MS, Wen J, Kumar S, Campbell GR, Herzog N. Siderotic cerebral macrophages in the acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1992;116:509–516
  53. Morris CM, Kerwin JM, Edwardson JA. Non-haem iron histochemistry of the normal and Alzheimer’s disease hippocampus. Neurodegeneration. 1994;3:267–275
  54. Levin MJ, Tuil D, Uzan G, Dreyfus J-C, Kahn A. Expression of the transferrin gene during development of non-hepatic tissues (High levels of transferrin mRNA in fetal muscle and adult brain). Biochem Biophys Res Commun. 1984;122:212–217
  55. Bartlett WP, Li X-S, Connor JR. Expression of transferrin mRNA in the CNS of normal and jimpy mice. J Neurochem. 1991;57:318–322
  56. Dickinson TK, Connor JR. Transferrin, Ferritin and Iron in selected brain regions of hypotransferrinemic mice. J Comp Neurol. 1995;355:67–80
  57. Espinosa de los Monteros A, Kumar S, Scully S. Transferrin gene expression and secretion by rat brain cells in vitro. J Neurosci Res. 1990;18:299–304
  58. de Arriba Zerpa GA, Saleh M-C, Fernandez PM, et al.  Alternative splicing prevents transferrin secretion during differentiation of a human oligodendrocyte cell line. J Neurosci Res. 2000;61:388–395
  59. Tu G-F, Achen MG, Aldred AR, Southwell BR, Schreiber G. The distribution of cerebral expression of the transferrin gene is species specific. J Biol Chem. 1991;266:1–8
  60. Dickson PW, Aldred AR, Marley PD, Guo-Fen T, Howlett GJ, Schreiber G. High prealbumin and transferrin mRNA levels in the choroid plexus of rat brain. Biochem Biophys Res Comm. 1985;127:890–895
  61. Connor JR, Phillips TM, Lakshman MR, Barron KD, Fine RE, Csiza CK. Regional variation in the levels of transferrin in the central nervous system of normal and myelin-deficient rats. J Neurochem. 1987;49:1523–1529
  62. Hill JM, Ruff MR, Weber RJ, Pert CB. Transferrin receptors in rat brain (Neuropeptide-like pattern and relationship to iron distribution). Proc Natl Acad Sci USA. 1985;82:4553–4557
  63. Mash DC, Pablo J, Flynn DD, Efange SNBM, Weiner WJ. Characterization and distribution of transferrin receptors in the rat brain. J Neurochem. 1990;55:1972–1979
  64. Hulet SW, Hess EJ, Debinski W, et al.  Characterization and distribution of ferritin binding sites in the adult mouse brain. J Neurochem. 1999;72:868–874
  65. Hulet SW, Powers S, Connor JR. Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J Neurol Sci. 1999;165:48–55
  66. Moos T. Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system. J Comp Neurol. 1996;375:675–692
  67. Dickinson TK, Connor JR. Immunohistochemical analysis of transferrin receptor (regional and cellular distribution in the hypotransferrinemic (hpx) mouse brain). Brain Res. 1998;801:171–181
  68. Dickinson TK, Connor JR. Histological analysis of selected brain regions of hypotransferrinemic mice. Brain Res. 1994;635:169–178
  69. Idzerda RL, Huebers H, Finch CA, McKnight GS. Rat transferrin gene expression (tissue-specific regulation by iron deficiency). Proc Natl Acad Sci USA. 1986;83:3723–3727
  70. Malecki EA, Devenyi AG, Beard JL, Connor JR. Transferrin response in normal and iron deficient mice heterozygotic for hypotransferrinemia (effects on iron and manganese accumulation). BioMetals. 1998;11:265–276
  71. Levi S, Yewdall SJ, Harrison PM, et al.  Evidence that H- and L-chains have cooperative roles in the iron-uptake mechanism of human ferritin. Biochem J. 1992;288:591–596
  72. Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt P. A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzeimer’s diseased brains. J Neurochem. 1995;65:717–724
  73. Han J, Day JR, Thomspon K, Connor JR, Beard JL. Iron deficiency alters H and L ferritin subunits in rat brain. Cell Mol Biol. 2000;46:517–528
  74. Connor JR, Boeshore KL, Benkovic SA. Isoforms of ferritin have a specific cellular distribution in the brain. J Neurosci Res. 1994;37:461–465
  75. Gould RM, Freund CM, Palmer F, Feinstein DL. Messenger RNAs located in myelin sheath assembly sites. J Neurochem. 2000;75:1834–1844
  76. Percy ME, Wong S, Bauer S, et al.  Iron metabolism and human ferritin heavy chain cDNA from adult brain with an elongated untranslated region (New findings and insights). Analyst. 1998;123:41–50
  77. Cheepsunthorn P, Palmer C, Connor JR. Cellular distribution of ferritin subunits in postnatal rat brain. J Comp Neurol. 1998;400:73–86
  78. Sanyal B, Polak PE, Szuchet S. Differential expression of the heavy chain ferritin gene in non-adhered and adhered oligodendrocytes. J Neurosci Res. 1996;46:187–197
  79. Focht SJ, Snyder BS, Beard LJ, van Gelder W, Williams L, Connor JR. Regional distribution of iron, transferrin, ferritin and oxidatively modified proteins in young and aged Fischer 344 rat brains. Neuroscience. 1997;79:255–261
  80. Hu J, Connor JR. Characterization and identification of the iron regulatory protein in the brain. J Neurochem 1996;1996:67:838–44.
  81. Smith MA, Wehr K, Harris PLR, Siedlak SL, Connor JR, Perry G. Abnormal localization of iron regulatory protein in Alzheimer’s disease. Brain Res. 1998;788:232–236
  82. Piñero DJ, Hu J, Connor JR. Alterations in the interaction between iron regulatory proteins and their iron responsive element in normal and Alzheimer’s diseased brains. Cell Mol Biol (Noisy-Le-Grand). 2000;46:761–776
  83. Swaiman KF, Machen VL. Iron uptake by mammalian cortical neurons. Ann Neurol. 1984;16:66–70
  84. Faucheux BA, Nillesse N, Damier P, et al.  Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson’s disease. Proc Natl Acad Sci USA. 1995;92:9603–9607
  85. Kaur C, Ling EA. Transient expression of transferrin receptors and localization of iron in amoeboid microglia in postnatal rats. J Anat. 1995;186:165–173
  86. Jefferies W, Brandon M, Hunt S, Williams A, Gatter K, Mason D. Transferrin receptor on endothelium of brain capillaries. Nature. 1984;312:162–163
  87. Fishman J, Rubin J, Handrahan J, Connor J, Fine R. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res. 1987;18:299–304
  88. Descamps L, Dehouck MP, Torpier G, Cecchelli R. Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells. Am J Physiol. 1996;270:1149–1158
  89. Crowe A, Morgan EH. Iron and transferrin uptake by brain and cerebrospinal fluid in the rat. Brain Res. 1992;592:8–16
  90. Banks WA, Kastin AJ, Fasold MB, Barrera CM, Augereau G. Studies of the slow bidirectional transport of iron and transferrin across the blood-brain barrier. Brain Res Bull. 1988;21:881–885
  91. Roberts RL, Fine RE, Sandra A. Receptor-mediated endocytosis of transferrin at the blood-brain barrier. J Cell Sci. 1993;104:521–532
  92. Gunshin H, Mackenzie B, Berger UV, et al.  Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–488
  93. Oates PS, Morgan EH. Defective iron uptake by the duodenum of Belgrade rats fed diets of different iron contents. Am J Physiol. 1996;270:826–832
  94. Takeda A, Akiyama T, Sawashita J, Okada S. Brain uptake of trace metals, zinc and manganese, in rats. Brain Res. 1994;640:341–344
  95. Malecki EA, Cook BM, Devenyi AG, Beard JL, Connor JR. Transferrin is required for normal distribution of 59Fe and 54Mn in mouse brain. J Neurol Sci. 1999;170:112–118
  96. Dwork AJ. Effects of diet and development upon the uptake and distribution of cerebral iron. J Neurol Sci. 1995;134(Suppl):45–51
  97. Barfield CP, Yu VY, Noma O, et al.  Cerebral blood volume measured using near-infrared spectroscopy and radiolabels in the immature lamb brain. Pediatr Res. 1999;46:50–56
  98. Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology. 2000;54:1698–1700
  99. Levine SM, Lynch SG, Ou C-N, Wulser MJ, Tam E, Boo N. Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients. Brain Res. 1999;821:511–515
  100. Broadwell RD, Baker-Cairns BJ, Friden PM, Oliver C, Villegas JC. Transcytosis of protein through the mammalian cerebral epithelium and endothelium. III. Receptor-mediated transcytosis through the blood-brain barrier of blood-borne transferrin and antibody against the transferrin receptor. Exp Neurol. 1996;142:47–65
  101. Benkovic SA, Connor JR. Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain. J Comp Neurol. 1993;338:97–113
  102. Moos T. Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system. J Comp Neurol. 1996;375:675–692
  103. Moos T, Morgan EH. Kinetics and distribution of [59Fe-125I]transferrin injected into the ventricular system of the rat. Brain Res. 1998;790:115–128
  104. Dickinson TK, Devenyi AG, Connor JR. Distribution of injected 59Fe and 54Mn in hypotransferrinemic mice. J Lab Clin Med. 1996;128:270–278

PII: S0887-8994(01)00303-4

Pediatric Neurology
Volume 25, Issue 2 , Pages 118-129 , August 2001