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Iron Deficiency and Overload pp 181–193Cite as

Iron-Metabolism in Neurons of the Motor System of the Central Nervous System: Lessons from Iron Deficiency and Overloading Pathologies

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Part of the book series: Nutrition and Health ((NH))

Summary

• A massive expression of the transferrin receptor ensures uptake of iron by neurons in the brain.

• Oligodendrocytes do not contain transferrin receptors, which brings into question whether they are less capable of extracting iron under conditions where there is a shortage of iron as compared to that of neurons.

• The impaired synthesis of myelin by oligodendrocytes is the key responsible factor for impaired motor function in iron deficiency.

• In conditions with iron overload in the brain, ferritin expressed by microglia, and possibly also neurons, is responsible for scavenging excess iron which causes oxidative stress and damage to brain cells.

• New objectives for understanding iron homeostasis in the brain should be directed toward iron uptake and intracellular transport in oligodendrocytes to learn more about why these cells are so affected by iron deficiency. In conditions with iron overload, relevant studies should include looking at possible scavenging processes that prevent iron toxicity, e.g., do neurons raise their levels of ferritin and ferroportin to increase storage and export of iron, respectively?

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Abbreviations

CNS:

Central nervous system

DMT1:

Divalent metal transporter I

PNS:

Peripheral nervous system (PNS)

References

  • Abboud, S., & Haile, D. J. (2000). A novel mammalian iron-regulated protein involved in intracellular iron metabolism. Journal of Biological Chemistry, 275, 19906–19912.

    Article  PubMed  CAS  Google Scholar 

  • Ashkenazi, R., Ben-Shachar, D., & Youdim, M. B. (1982) Nutritional iron and dopamine binding sites in the rat brain. Pharmacology, Biochemistry, and Behavior, 17(Suppl. 1), 43–47.

    Article  PubMed  CAS  Google Scholar 

  • Bartzokis, G., Cummings, J. L., Markham, C. H., Marmarelis, P. Z., Treciokas, L. J., Tishler, T. A., et al. (1999). MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects. Magnetic Resonance Imaging, 17, 213–222.

    Article  PubMed  CAS  Google Scholar 

  • Beard, J. L., Wiesinger, J. A., & Connor, J. R. (2003). Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Developmental Neuroscience, 25, 308–315.

    Article  PubMed  CAS  Google Scholar 

  • Beard, J. L., Wiesinger, J. A., & Jones, B. C. (2006). Cellular iron concentrations directly affect the expression levels of norepinephrine transporter in PC12 cells and rat brain tissue. Brain Research, 1092, 47–58.

    Article  PubMed  CAS  Google Scholar 

  • Beard, J. L., Unger, E. L., Bianco, L. E., Paul, T., Rundle, S. E., & Jones, B. C. (2007). Early postnatal iron repletion overcomes lasting effects of gestational iron deficiency in rats. Journal of Nutrition, 137, 1176–1182.

    PubMed  CAS  Google Scholar 

  • Benkovic, S. A., & Connor, J. R. (1993). Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain. Journal of Comperative Neurology, 338, 97–113.

    Article  CAS  Google Scholar 

  • Borges, L. F., Elliott, P. J., Gill, R., Iversen, S. D., & Iversen, L. L.(1985). Selective extraction of small and large molecules from the cerebrospinal fluid by Purkinje neurons. Science, 228, 346–348.

    Article  PubMed  CAS  Google Scholar 

  • Broadwell, R. D., & Brightman, M. W. (1976). Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. Journal of Comperative Neurology, 166, 257–283.

    Article  CAS  Google Scholar 

  • Burdo, J. R., Menzies, S. L., Simpson, I. A., Garrick, L. M., Garrick, M. D., Dolan, K. G., et al. (2001). Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. Journal of Neuroscience Research, 66, 1198–1207.

    Article  PubMed  CAS  Google Scholar 

  • Burhans, M. S., Dailey, C., Beard, Z., Wiesinger, J., Murray-Kolb, L., Jones, B. C., et al. (2005). Iron deficiency: Differential effects on monoamine transporters. Nutritional Neuroscience, 8, 31–38.

    Article  PubMed  CAS  Google Scholar 

  • Chi, S. I., Wang, C. K., Chen, J. J., Chau, L. Y., & Lin, T. N. (2000). Differential regulation of H- and L-ferritin messenger RNA subunits, ferritin protein and iron following focal cerebral ischemia-reperfusion. Neuroscience, 100, 475–484.

    Article  PubMed  CAS  Google Scholar 

  • Connor, J. R., & Fine, R. E. (1987). Development of transferrin-positive oligodendrocytes in the rat central nervous system. Journal of Neuroscience Research, 17, 51–59.

    Article  PubMed  CAS  Google Scholar 

  • Cook, J. L., Marcheselli, V., Alam, J., Deininger, P. L., & Bazan, N. G. (1998). Temporal changes in gene expression following cryogenic rat brain injury. Molecular Brain Research, 55, 9–19.

    Article  PubMed  CAS  Google Scholar 

  • Crichton, R. R., Wilmet, S., Legssyer, R., & Ward, R. J. (2002). Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. Journal of Inorganic Biochemistry, 91, 9–18.

    Article  PubMed  CAS  Google Scholar 

  • Curtis, A. R., Fey, C., Morris, C. M., Bindoff, L. A., Ince, P. G., Chinnery, P. F., et al. (2001). Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nature Genetics, 28, 350–354.

    Article  PubMed  CAS  Google Scholar 

  • Dallman, P. R., & Spirito, R. A. (1977). Brain iron in the rat: extremely slow turnover in normal rats may explain long-lasting effects of early iron deficiency. Journal of Nutrition, 107, 1075–1081.

    PubMed  CAS  Google Scholar 

  • Dexter, D. T., Wells, F. R., Agid, F., Agid, Y., Lees, A. J., Jenner, P., et al. (1987). Increased nigral iron content in postmortem parkinsonian brain. Lancet, 2, 1219–1220.

    Article  PubMed  CAS  Google Scholar 

  • Dröge, W., & Schipper, H. M. (2007). Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell, 6, 361–370.

    Article  PubMed  Google Scholar 

  • Dwork, A. J., Lawler, G., Zybert, P. A., Durkin, M., Osman, M., Willson, N., et al. (1990). An autoradiographic study of the uptake and distribution of iron by the brain of the young rat. Brain Research, 518, 31–39.

    Article  PubMed  CAS  Google Scholar 

  • Focht, S. J., Snyder, B. S., Beard, J. L., Van Gelder, W., Williams, L. R., & Connor, J. R. (1997). Regional distribution of iron, transferrin, ferritin, and oxidatively modified proteins in young and aged Fischer 344 rat brains. Neuroscience, 79, 255–261.

    Article  PubMed  CAS  Google Scholar 

  • Gocht, A., Keith, A. B., Candy, J. M., & Morris, C. M. (1993). Iron uptake in the brain of myelin-deficient rat. Neuroscience Letters, 154, 187–190.

    Article  PubMed  CAS  Google Scholar 

  • Graeber, M. B., Raivich, G., & Kreutzberg, G. W. (1989). Increase of transferrin receptors and iron uptake in regenerating motor neurons. Journal of Neuroscience Research, 23, 342–345.

    Article  PubMed  CAS  Google Scholar 

  • Hansen, T. M., Nielsen, H., Bernth, N., & Moos, T. (1999). Expression of ferritin protein and subunit mRNAs in normal and iron deficient rat brain. Molecular Brain Research, 65, 186–197.

    Article  PubMed  CAS  Google Scholar 

  • Jiang, Y., Wu, J., Keep, R. F., Hua, Y., Hoff, J. T., & Xi, G. (2002). Hypoxia-inducible factor-1alpha accumulation in the brain after experimental intracerebral hemorrhage. Journal of cerebral blood flow and metabolism, 22, 689–696.

    PubMed  CAS  Google Scholar 

  • Ke, Y., & Qian, Z. M. (2003). Iron misregulation in the brain: A primary cause of neurodegenerative disorders. Lancet Neurology, 2, 246–253.

    Article  PubMed  CAS  Google Scholar 

  • Ke, Y., Chang, Y. Z., Duan, X. L., Du, J. R., Zhu, L., Wang, K., et al. (2005). Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain. Neurobiology of Aging, 26, 739–748.

    Article  PubMed  CAS  Google Scholar 

  • Kotzbauer, P. T., Truax, A. C., Trojanowski, J. Q., & Lee, V. M. (2005). Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. Journal of Neuroscience, 25, 689–698.

    Article  PubMed  CAS  Google Scholar 

  • Kühn, L. C. (1998). Iron and gene expression: Molecular mechanisms regulating cellular iron homeostasis. Nutrition Review, 56, s11–s19.

    Article  Google Scholar 

  • Lin, H. H., Snyder, B. S., & Connor, J. R. (1990). Transferrin expression in myelinated and non-myelinated peripheral nerves. Brain Research, 526, 217–220.

    Article  PubMed  CAS  Google Scholar 

  • Loeffler, D. A., Connor, J. R., Juneau, P. L., Snyder, B. S., Kanaley, L., DeMaggio, A. J., et al. (1995). Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions. Journal of Neurochemistry, 65, 710–724.

    Article  PubMed  CAS  Google Scholar 

  • Lok, C. N., & Ponka, P. (2000). Identification of a hypoxia response element in the transferrin receptor gene. Journal of Biological Chemistry, 274, 24147–24152.

    Article  Google Scholar 

  • Lykkesfeldt, J., Morgan, E., Christen, S., Skovgaard, L. T., & Moos, T. (2007). Oxidative stress and damage in liver, but not in brain, of Fischer 344 rats subjected to dietary iron supplementation with lipid-soluble [(3,5,5-trimethylhexanoyl)ferrocene]. Journal of biochemical and molecular toxicology, 21, 145–155.

    Article  PubMed  CAS  Google Scholar 

  • MacKenzie, E. L., Iwasaki, K., & Tsuji, Y. (2008). Intracellular iron transport and storage: From molecular mechanisms to health implications. Antioxidants & Redox Signaling, 10, 997–1030.

    Article  CAS  Google Scholar 

  • Malik, I., Turk, J., Mancuso, D. J., Montier, L., Wohltmann, M., Wozniak, D. F., et al. (2008). Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. American Journal of Pathology, 172, 406–416.

    Article  PubMed  CAS  Google Scholar 

  • Mancuso, M., Davidzon, G., Kurlan, R. M., Tawil, R., Bonilla, E., Di Mauro, S., & et al. (2005). Hereditary ferritinopathy: A novel mutation, its cellular pathology, and pathogenic insights. Journal of Neuropathology and Experimental Neurology, 64, 280–294.

    PubMed  CAS  Google Scholar 

  • Meyron-Holtz, E. G., Ghosh, M. C., & Rouault, T. A. (2004). Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science, 306, 2087–2090.

    Article  PubMed  CAS  Google Scholar 

  • Mirza, B., Hadberg, H., Thomsen, P., & Moos, T. (2000). The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. Neuroscience, 95, 425–432.

    Article  PubMed  CAS  Google Scholar 

  • Moos, T. (1995). Age-dependent uptake and retrograde axonal transport of exogenous albumin and transferrin in rat motor neurons. Brain Research, 672, 14–23.

    Article  PubMed  CAS  Google Scholar 

  • Moos, T. (1996). Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system. Journal of Comperative Neurology, 375, 675–692.

    Article  CAS  Google Scholar 

  • Moos, T., & Høyer, P. E. (1996). Detection of plasma proteins in CNS neurons: Conspicuous influence of tissue-processing parameters and the utilization of serum for blocking nonspecific reactions. Journal of Histochemistry and Cytochemistry, 44, 591–603.

    Article  PubMed  CAS  Google Scholar 

  • Moos, T., & Morgan, E. H. (1998a). Kinetics and distribution of [59Fe-125I]transferrin injected into the ventricular system of the rat. Brain Research, 790, 115–128.

    Article  PubMed  CAS  Google Scholar 

  • Moos, T., & Morgan, E. H. (1998b). Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. Journal of Neuroscience Research, 54, 486–494.

    Article  PubMed  CAS  Google Scholar 

  • Moos, T., & Morgan, E. H. (2002). A morphological study of the developmentally regulated transport of iron into the brain. Developmental Neuroscience, 24, 99–105.

    Article  PubMed  CAS  Google Scholar 

  • Moos, T., & Morgan, E. H. (2004a). The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain. Journal of Neurochemistry, 88, 233–245.

    Article  PubMed  CAS  Google Scholar 

  • Moos, T., & Morgan, E. H. (2004a). The metabolism of neuronal iron and its pathogenic role in neurological disease: Review. Annals of the New York Academy of Sciences, 1012, 14–26.

    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. Seminars in Pediatric Neurology, 13, 49–57.

    Article  Google Scholar 

  • Moos, T., Oates, P. S., & Morgan, E. H. (1998). Expression of the neuronal transferrin receptor is age dependent and susceptible to iron deficiency. Journal of Comperative Neurology, 398, 420–430.

    Article  CAS  Google Scholar 

  • Moos, T., Oates, P. S., & Morgan, E. H. (2001). Expression of transferrin mRNA in rat oligodendrocytes is iron-independent and changes with increasing age. Nutritional Neuroscience, 4, 15–23.

    PubMed  CAS  Google Scholar 

  • Moos, T., Rosengren Nielsen, T., Skjørringe, T., & Morgan, E. H. (2007). Iron trafficking inside the brain. Journal of Neurochemistry, 103, 1730–1740.

    Article  PubMed  CAS  Google Scholar 

  • Morgan, N. V., Westaway, S. K., Morton, J. E., Gregory, A., Gissen, P., Sonek, S., et al. (2006). PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nature Genetics, 38, 752–754.

    Article  PubMed  CAS  Google Scholar 

  • Omori, N., Maruyama, K., Jin, G., Li, F., Wang, S. J., Hamakawa, Y., et al. (2003). Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin. Neurological Research, 25, 275–279.

    Article  PubMed  CAS  Google Scholar 

  • Ortiz, E., Pasquini, J. M., Thompson, K., Felt, B., Butkus, G., Beard, J., et al. (2004). Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. Journal of Neuroscience Research, 77, 681–689.

    Article  PubMed  CAS  Google Scholar 

  • Russo, N., Edwards, M., Andrews, T., O'Brien, M., & Bhatia, K. P. (2004). Hereditary haemochromatosis is unlikely to cause movement disorders – A critical review. Journal of Neurology, 251, 849–852.

    Article  PubMed  Google Scholar 

  • Rouault, T. A., & Cooperman, S. (2006). Brain iron metabolism. Seminars in Pediatric Neurology, 13, 142–148.

    Article  PubMed  Google Scholar 

  • Salis, C., Setton, C. P., Soto, E. F., & Pasquini, J. M. (2007). The mRNA of transferrin is expressed in Schwann cells during their maturation and after nerve injury. Experimental Neurology, 207, 85–94.

    Article  PubMed  CAS  Google Scholar 

  • Sofic, E., Riederer, P., Heinsen, H., Beckmann, H., Reynolds, G. P., Hebenstreit, G., et al. (1988). Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. Journal of Neural Transmission, 74, 199–205.

    Article  PubMed  CAS  Google Scholar 

  • Taylor, E. M., & Morgan, E. H. (1990). Developmental changes in transferrin and iron uptake by the brain in the rat. Developmental Brain Research, 55, 35–42.

    Article  PubMed  CAS  Google Scholar 

  • Taylor, E. M., Crowe, A., & Morgan, E. H. (1991). Transferrin and iron uptake by the brain: effects of altered iron status. Journal of Neurochemistry, 57, 1584–1592.

    Article  PubMed  CAS  Google Scholar 

  • Vidal, R., Miravalle, L., Gao, X., Barbeito, A. G., Baraibar, M. A., Hekmatyar, S. K., et al. (2008). Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice. Journal of Neuroscience, 28, 60–67.

    Article  PubMed  CAS  Google Scholar 

  • Wagner, K. R., Sharp, F. R., Ardizzone, T. D., Lu, A., & Clark, J. F. (2003). Heme and iron metabolism: Role in cerebral hemorrhage. Journal of Cerebral Blood Flow and Metabolism, 23, 629–652.

    PubMed  CAS  Google Scholar 

  • Yehuda, S., Youdim, M. E., & Mostofsky, D. I. (1986). Brain iron-deficiency causes reduced learning capacity in rats. Pharmacology, Biochemistry, and Behaviour, 25, 141–144.

    Article  CAS  Google Scholar 

  • Yehuda, S., Rabinovitz, S., & Mostofsky, D. I. (2006). Nutritional deficiencies in learning and cognition. Journal of pediatric gastroenterology and nutrition (Supplement), 43(3), S22–S25.

    Article  CAS  Google Scholar 

  • Zhou, B., Westaway, S. K., Levinson, B., Johnson, M. A., Gitschier, J., & Hayflick, S. J. (2001). A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nature Genetics, 28, 345–349.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

S Peters is thanked for revising the manuscript. Data obtained by the authors were mainly sponsored by grants from the The Lundbeck Foundation, The Danish Parkinson’s Disease Organisation, and The Danish Medical Research Council.

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Authors and Affiliations

  1. Section of Neurobiology, Department of Health Science & Technology, Aalborg University, Aalborg, Denmark

    Torben Moos (MD, PHD, DMSC)

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  1. Torben Moos
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Editors and Affiliations

  1. Dept. Psychology, Bar-Ilan University, Ramat Gan, 52900, Israel

    Shlomo Yehuda

  2. Dept. Psychology, Boston University, Cummington St. 64, Boston, 02215-2407, USA

    David I. Mostofsky

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Moos, T. (2009). Iron-Metabolism in Neurons of the Motor System of the Central Nervous System: Lessons from Iron Deficiency and Overloading Pathologies. In: Yehuda, S., Mostofsky, D. (eds) Iron Deficiency and Overload. Nutrition and Health. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59745-462-9_10

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  • DOI: https://doi.org/10.1007/978-1-59745-462-9_10

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