Brain iron disorders

doi:10.1017/CBO9780511544873.061

60 - Brain iron disorders

from Part X - Other neurodegenerative diseases

Published online by Cambridge University Press: 04 August 2010

Anthony E. Lang and

Hiroaki Miyajima and

M. Flint Beal: Affiliation:
Cornell University, New York
Anthony E. Lang: Affiliation:
University of Toronto
Albert C. Ludolph: Affiliation:
Universität Ulm, Germany
Satoshi Kono: Affiliation:
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
Hiroaki Miyajima: Affiliation:
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
Jonathan D. Gitlin: Affiliation:
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

Book contents

Get access

Summary

Introduction

Iron is an essential transition metal required for the binding and activation of dioxygen in a series of critical transport and redox reactions. The facile electron chemistry of iron also accounts for the toxicity of this metal and therefore intricate pathways have evolved to allow for the transport, trafficking and compartmentalization of iron within cells (Kaplan, 2002a). These pathways prevent the formation of iron-induced reactive oxygen intermediates that contribute to the pathogenesis of tissue injury in inherited disorders of iron homeostasis such as hemochromatosis with resultant cirrhosis, diabetes and cardiac failure (Lee et al., 2002). Within the central nervous system, iron is required for critical, diverse processes including neurotransmitter biosynthesis, myelin formation and nitric oxide signaling, as well as oxidative phosphorylation essential for sustaining brain energy requirements (Sipe et al., 2002). Despite this critical role of iron in brain function, the molecular and cellular details of iron metabolism within the human central nervous system remain poorly understood.

Iron uptake into the brain is dependent upon plasma transferrin and transferrin receptors localized to the microvasculature. Although both the apical membrane divalent iron transporter DMT1 and the basolateral transporter ferroportin are expressed within the central nervous system, the precise role of these proteins in brain iron homeostasis is currently unknown (Sipe et al., 2002). The intracellular iron binding protein ferritin is abundantly expressed in neurons and glia and presumably serves as the major source of iron storage within these cells.

Type: Chapter
Information: Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
, pp. 880 - 889

DOI: https://doi.org/10.1017/CBO9780511544873.061 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2005

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Abboud, S. & Haile, D. J. (2000). A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275, 19906–12CrossRef Google Scholar PubMed

Andrews, N. C. (2000). Iron metabolism: iron deficiency and iron overload. Annu. Rev. Genom. Hum. Genet., 1, 75–98CrossRef Google Scholar PubMed

Andrews, N. C. (2002). A genetic view of iron homeostasis. Semin. Hematol. 39, 227–34CrossRef Google Scholar PubMed

Askwith, C. D., Eide, A., Ho, P. S.et al. (1994). The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell, 76, 403–10CrossRef Google Scholar PubMed

Bosio, S., Gobbi, M., Roetto, A.et al. (2002). Anemia and iron overload due to compound heterozygosity for novel ceruloplasmin mutations. Blood, 100, 2246–8CrossRef Google Scholar PubMed

Calabrese, L., Carbonaro, M. & Musci, G. (1989). Presence of coupled trinuclear copper cluster in mammalian ceruloplasmin is essential for efficient electron transfer to oxygen. J. Biol. Chem., 264, 6183–7Google Scholar

Craven, C. M., Alexander, J., Eldridge, M.Kushner, J. P.Bernstein, S. & Kaplan, J. (1987). Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. Proc. Natl Acad. Sci., USA, 84, 3457–61CrossRef Google Scholar PubMed

Crompton, D. E., Chinnery, P. F., Fey, C.et al. (2002). Neuroferritinopathy: a window on the role of iron in neurodegeneration. Blood Cells Mol. Dis., 29, 522–31CrossRef Google Scholar PubMed

Curtis, A. R., Fey, C., Morris, C. M.et al. (2001). Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet., 28, 350–4CrossRef Google Scholar PubMed

Daimon, M., Kato, T., Kawanami, T.et al. (1995a). A nonsense mutation of the ceruloplasmin gene in hereditary ceruloplasmin deficiency with diabetes mellitus. Biochem. Biophys. Res. Commun., 217, 89–95CrossRef Google Scholar

Daimon, M., Yamatani, K., Igarashi, M.et al. (1995b). Fine structure of the human ceruloplasmin gene. Biochem. Biophys. Res. Commun., 208, 1028–35CrossRef Google Scholar

Daimon, M., Moriai, S., Susa, S., Yamatani, K., Hosoya, T. & Kato, T. (1999). Hypocaeruloplasminaemia with heteroallelic caeruloplasmin gene mutation: MRI of the brain. Neuroradiology, 41, 185–7CrossRef Google Scholar

Daimon, M., Susa, S., Ohizumi, T.et al. (2000). A novel mutation of the ceruloplasmin gene in a patient with heteroallelic ceruloplasmin gene mutation (HypoCPGM). Tohoku J. Exp. Med., 191, 119–25CrossRef Google Scholar

Donovan, A., Brownlie, A., Zhou, Y.et al. (2000). Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature, 403, 776–81CrossRef Google Scholar PubMed

Fortna, R. R., Watson, H. A. & Nyquist, S. E. (1999). Glycosyl phosphatidylinositol-anchored ceruloplasmin is expressed by rat Sertoli cells and is concentrated in detergent-insoluble membrane fractions. Biol. Reprod., 61, 1042–9CrossRef Google Scholar PubMed

Gitlin, J. D. (1998). Aceruloplasminemia. Pediatr. Res., 44, 271–6CrossRef Google Scholar PubMed

Harris, Z. L., Durley, A. P., Man, T. K. & Gitlin, J. D. (1999). Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl Acad. Sci., USA, 96, 10812–17CrossRef Google Scholar PubMed

Harris, Z. L., Takahashi, Y., Miyajima, H., Serizawa, M., MacGillivray, R. T. & Gitlin, J. D. (1995). Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc. Natl Acad. Sci., USA, 92, 2539–43CrossRef Google Scholar PubMed

Harris, Z. L., Migas, M. C., Hughes, A. E., Logan, J. L. & Gitlin, J. D. (1996). Familial dementia due to a frameshift mutation in the caeruloplasmin gene. Quart. J. Med., 89, 355–9CrossRef Google Scholar

Harris, Z. L., Klomp, L. W. & Gitlin, J. D. (1998). Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Am. J. Clin. Nutr., 67, 972S–7SCrossRef Google Scholar PubMed

Hayflick, S. J., Westaway, S. K., Levinson, B.et al. (2003). Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N. Engl. J. Med., 348, 33–40CrossRef Google Scholar PubMed

Hellman, N. E. & Gitlin, J. D. (2002). Ceruloplasmin metabolism and function. Annu. Rev. Nutr., 22, 439–58CrossRef Google Scholar PubMed

Hellman, N. E., Schaefer, M., Gehrke, S.et al. (2000). Hepatic iron overload in aceruloplasminaemia. Gut, 47, 858–60CrossRef Google Scholar PubMed

Hellman, N. E., Kono, S., Mancini, G. M., Hoogeboom, A. J., Jong, G. J. & Gitlin, J. D. (2002a). Mechanisms of copper incorporation into human ceruloplasmin. J. Biol. Chem., 277, 46632–8CrossRef Google Scholar

Hellman, N. E., Kono, S., Miyajima, H. & Gitlin, J. D. (2002b). Biochemical analysis of a missense mutation in aceruloplasminemia. J. Biol. Chem., 277, 1375–80CrossRef Google Scholar

Jeong, S. Y. & David, S. (2003). GPI-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J. Biol. Chem.

Kaneko, K., Yoshida, K., Arima, K.et al. (2002). Astrocytic deformity and globular structures are characteristic of the brains of patients with aceruloplasminemia. J. Neuropathol. Exp. Neurol., 61, 1069–77CrossRef Google Scholar PubMed

Kaplan, J. (2002a). Mechanisms of cellular iron acquisition: another iron in the fire. Cell, 111, 603–6CrossRef Google Scholar

Kaplan, J. (2002b). Strategy and tactics in the evolution of iron acquisition. Semin. Hematol., 39, 219–26CrossRef Google Scholar

Kato, T., Daimon, M., Kawanami, T., Ikezawa, Y., Sasaki, H. & Maeda, K. (1997). Islet changes in hereditary ceruloplasmin deficiency. Hum. Pathol., 28, 499–502CrossRef Google Scholar PubMed

Kaur, D., Yantiri, F., Rajagopalan, S.et al. (2003). Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron, 37, 899–909CrossRef Google Scholar PubMed

Klomp, L. W. & Gitlin, J. D. (1996). Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum. Mol. Genet., 5, 1989–96CrossRef Google Scholar PubMed

Klomp, L. W., Farhangrazi, Z. S., Dugan, L. L. & Gitlin, J. D. (1996). Ceruloplasmin gene expression in the murine central nervous system. J. Clin. Invest., 98, 207–15CrossRef Google Scholar PubMed

Kohno, S., Miyajima, H., Takahashi, Y. & Inoue, Y. (2000). Aceruloplasminemia with a novel mutation associated with parkinsonism. Neurogenetics, 2, 237–8CrossRef Google Scholar PubMed

Koschinsky, M. L., Chow, B. K., Schwartz, J., Hamerton, J. L. & MacGillivray, R. T. (1987). Isolation and characterization of a processed gene for human ceruloplasmin. Biochemistry, 26, 7760–7CrossRef Google Scholar PubMed

Lee, G. R., Nacht, S., Lukens, J. N. & Cartwright, G. E. (1968). Iron metabolism in copper-deficient swine. J. Clin. Invest., 47, 2058–69CrossRef Google Scholar PubMed

Lee, P., Gelbart, T., West, C., Halloran, C. & Beutler, E. (2002). Seeking candidate mutations that affect iron homeostasis. Blood Cells Mol. Dis., 29, 471–87CrossRef Google Scholar PubMed

Logan, J. I., Harveyson, K. B., Wisdom, G. B., Hughes, A. E. & Archbold, G. P. (1994). Hereditary caeruloplasmin deficiency, dementia and diabetes mellitus. Quart. J. Med., 87, 663–70Google Scholar PubMed

Loreal, O., Turlin, B., Pigeon, C.et al. (2002). Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J. Hepatol., 36, 851–6CrossRef Google Scholar PubMed

McKie, A. T., Marciani, P., Rolfs, A.et al. (2000). A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cel., 5, 299–309CrossRef Google Scholar PubMed

Miyajima, H., Nishimura, Y., Mizoguchi, K., Sakamoto, M., Shimizu, T. & Honda, N. (1987). Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology, 37, 761–7CrossRef Google Scholar PubMed

Miyajima, H., Takahashi, Y., Kamata, T., Shimizu, H., Sakai, N. & Gitlin, J. D. (1997). Use of desferrioxamine in the treatment of aceruloplasminemia. Ann. Neurol., 41, 404–7CrossRef Google Scholar PubMed

Miyajima, H., Fujimoto, M., Kohno, S., Kaneko, E. & Gitlin, J. D. (1998). CSF abnormalities in patients with aceruloplasminemia. Neurology, 51, 1188–90CrossRef Google Scholar PubMed

Miyajima, H., Kohno, S., Takahashi, Y., Yonekawa, O. & Kanno, T. (1999). Estimation of the gene frequency of aceruloplasminemia in Japan. Neurology, 53, 617–19CrossRef Google Scholar PubMed

Miyajima, H., Kono, S., Takahashi, Y., Sugimoto, M., Sakamoto, M. & Sakai, N. (2001). Cerebellar ataxia associated with heteroallelic ceruloplasmin gene mutation. Neurology, 57, 2205–10CrossRef Google Scholar PubMed

Miyajima, H., Kono, S., Takahashi, Y. & Sugimoto, M. (2002). Increased lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains. Blood Cells Mol. Dis., 29, 433–8CrossRef Google Scholar PubMed

Miyajima, H., Takahashi, Y. & Kono, S. (2003). Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals, 16, 205–13CrossRef Google Scholar PubMed

Montosi, G., Donovan, A., Totaro, A.et al. (2001). Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J. Clin. Invest., 108, 619–23CrossRef Google Scholar PubMed

Morita, H., Ikeda, S., Yamamoto, K.et al. (1995). Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann. Neurol., 37, 646–56CrossRef Google Scholar PubMed

Nittis, T. & Gitlin, J. D. (2002). The copper-iron connection: hereditary aceruloplasminemia. Semin. Hematol., 39, 282–9CrossRef Google Scholar PubMed

Njajou, O. T., Vaessen, N., Joosse, M.et al. (2001). A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat. Genet., 28, 213–14CrossRef Google Scholar PubMed

Okamoto, N., Wada, S., Oga, T.et al. (1996). Hereditary ceruloplasmin deficiency with hemosiderosis. Hum. Genet., 97, 755–8CrossRef Google Scholar PubMed

Osaki, S., Johnson, D. A. & Frieden, E. (1966). The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J. Biol. Chem., 241, 2746–51Google Scholar PubMed

Osaki, S., Johnson, D. A. & Frieden, E. (1971). The mobilization of iron from the perfused mammalian liver by a serum copper enzyme, ferroxidase I. J. Biol. Chem., 246, 3018–23Google Scholar PubMed

Patel, B. N. & David, S. (1997). A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes. J. Biol. Chem., 272, 20185–90CrossRef Google Scholar PubMed

Patel, B. N., Dunn, R. J. & David, S. (2000). Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J. Biol. Chem., 275, 4305–10CrossRef Google Scholar PubMed

Patel, B. N., Dunn, R. J., Jeong, S. Y., Zhu, Q., Julien, J. P. & David, S. (2002). Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J. Neurosci., 22, 6578–86CrossRef Google Scholar PubMed

Roeser, H. P., Lee, G. R., Nacht, S. & Cartwright, G. E. (1970). The role of ceruloplasmin in iron metabolism. J. Clin. Invest., 49, 2408–17CrossRef Google Scholar PubMed

Sato, M. & Gitlin, J. D. (1991). Mechanisms of copper incorporation during the biosynthesis of human ceruloplasmin. J. Biol. Chem., 266, 5128–34Google Scholar PubMed

Sipe, J. C., Lee, P. & Beutler, E. (2002). Brain iron metabolism and neurodegenerative disorders. Dev. Neurosci., 24, 188–96CrossRef Google Scholar PubMed

Takahashi, Y., Miyajima, H., Shirabe, S., Nagataki, S., Suenaga, A. & Gitlin, J. D. (1996). Characterization of a nonsense mutation in the ceruloplasmin gene resulting in diabetes and neurodegenerative disease. Hum. Mol. Genet., 5, 81–4CrossRef Google Scholar PubMed

Takeuchi, Y., Yoshikawa, M., Tsujino, T.et al. (2002). A case of aceruloplasminaemia: abnormal serum ceruloplasmin protein without ferroxidase activity. J. Neurol. Neurosurg. Psychiatr., 72, 543–5Google Scholar PubMed

Torti, F. M. & Torti, S. V. (2002). Regulation of ferritin genes and protein. Blood, 99, 3505–16CrossRef Google Scholar

Vulpe, C. D., Kuo, Y. M., Murphy, T. L.et al. (1999). Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet., 21, 195–9CrossRef Google Scholar PubMed

Yazaki, M., Yoshida, K., Nakamura, A.et al. (1998). A novel splicing mutation in the ceruloplasmin gene responsible for hereditary ceruloplasmin deficiency with hemosiderosis. J. Neurol. Sci., 156, 30–4CrossRef Google Scholar PubMed

Yonekawa, M., Okabe, T., Asamoto, Y. & Ohta, M. (1999). A case of hereditary ceruloplasmin deficiency with iron deposition in the brain associated with chorea, dementia, diabetes mellitus and retinal pigmentation: administration of fresh-frozen human plasma. Eur. Neurol., 42, 157–62CrossRef Google Scholar PubMed

Yoshida, K., Furihata, K., Takeda, S.et al. (1995). A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat. Genet., 9, 267–72CrossRef Google Scholar PubMed

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. Nat. Genet., 28, 345–9CrossRef Google Scholar PubMed