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• W2036545911 abstract "Ceruloplasmin is a copper-binding protein, which is the major ferroxidase in plasma of hepatic origin. We now provide evidence for a novel membrane-bound form of ceruloplasmin expressed by astrocytes in the mammalian central nervous system. Using a monoclonal antibody (1A1), we show that the cell surface antigen recognized by this antibody is ceruloplasmin and that it is directly anchored to the cell surface via a glycosylphosphatidylinositol (GPI) anchor. Our peptide mapping and other immunochemical studies indicate that, except for the GPI anchor, the membrane-bound and secreted plasma forms are similar. We also show that the membrane-bound form of ceruloplasmin has oxidase activity. These studies therefore suggest that the GPI-anchored form of ceruloplasmin may play a role similar to the secreted form in oxidizing ferrous iron. The GPI-anchored form of ceruloplasmin expressed by astrocytes is likely to be the major form of this molecule in the central nervous system because serum ceruloplasmin does not cross the blood-brain barrier. Lack of this form of ceruloplasmin in the central nervous system could lead to the generation of highly toxic free radicals, which can cause neuronal degeneration as seen in aceruloplasminemia and other neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Ceruloplasmin is a copper-binding protein, which is the major ferroxidase in plasma of hepatic origin. We now provide evidence for a novel membrane-bound form of ceruloplasmin expressed by astrocytes in the mammalian central nervous system. Using a monoclonal antibody (1A1), we show that the cell surface antigen recognized by this antibody is ceruloplasmin and that it is directly anchored to the cell surface via a glycosylphosphatidylinositol (GPI) anchor. Our peptide mapping and other immunochemical studies indicate that, except for the GPI anchor, the membrane-bound and secreted plasma forms are similar. We also show that the membrane-bound form of ceruloplasmin has oxidase activity. These studies therefore suggest that the GPI-anchored form of ceruloplasmin may play a role similar to the secreted form in oxidizing ferrous iron. The GPI-anchored form of ceruloplasmin expressed by astrocytes is likely to be the major form of this molecule in the central nervous system because serum ceruloplasmin does not cross the blood-brain barrier. Lack of this form of ceruloplasmin in the central nervous system could lead to the generation of highly toxic free radicals, which can cause neuronal degeneration as seen in aceruloplasminemia and other neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Iron plays an important role as a cofactor for various enzymes, such as the cytochromes of the electron transport chain and ribonucleotide reductase. On the other hand, free iron can generate highly toxic free radicals because it is a redox-active transition metal (1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar). A number of enzymes, binding proteins, and transporters have been identified that are involved in mobilizing, transporting, and sequestering iron (1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar, 2Jefferies W.A. Gabathuler R. Rothenberger S. Food M. Kennard M.L. Trends Cell Biol. 1996; 6: 223-228Abstract Full Text PDF PubMed Scopus (20) Google Scholar, 3Kaplan J. O'Halloran T.V. Science. 1996; 271: 1510-1512Crossref PubMed Scopus (124) Google Scholar). Recent studies on the yeastSaccharomyces cerevisiae have resulted in the identification of several proteins, such as Fet3 and Ftr1, which directly participate in iron transport in this organism (4Askwith C. Eide D. Van Ho A. Bernard P.S. Li L. Davis Kaplan S. Sipe D.M. Kaplan J. Cell. 1994; 76: 403-410Abstract Full Text PDF PubMed Scopus (582) Google Scholar, 5De Silva D.M. Askwith C.C. Eide D. Kaplan J. J. Biol. Chem. 1995; 270: 1098-1101Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 6Stearman R. Yuan D.S. Yamaguchi-Iwai Y. Klausner R.D. Dancis A. Science. 1996; 271: 1552-1557Crossref PubMed Scopus (574) Google Scholar). The mammalian homologues of many of these proteins have yet to be identified. Ceruloplasmin, the major ferroxidase of plasma (300–450 μg/ml), is required for iron transport by transferrin. The oxidation of ferrous iron (Fe(II)) to ferric iron (Fe(III)) mediated by ceruloplasmin is necessary for iron incorporation into transferrin, since transferrin only binds the ferric form of iron. As a ferroxidase, ceruloplasmin might also play a role in a transferrin-independent iron uptake system, such as the one identified by Kaplan and colleagues (7Sturrock A. Alexander J. Lamb J. Craven C.M. Kaplan J. J. Biol. Chem. 1990; 265: 3139-3145Abstract Full Text PDF PubMed Google Scholar), which requires reduction of iron at the cell surface (reviewed in Ref. 1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar).Direct evidence for the role of ceruloplasmin in iron metabolism comes from studies of individuals with aceruloplasminemia, a hereditary deficiency of ceruloplasmin (8Miyajima H. Nishimura Y. Mizoguchi K. Sakamoto M. Shimizu T. Honda N. Neurology. 1987; 37: 761-767Crossref PubMed Google Scholar, 9Logan J.I. Harveyson K.B. Wisdom G.B. Hughes A.E. Archbold G.P.R. Q. J. Med. 1994; 87: 663-670Google Scholar, 10Harris Z.L. Takahashi Y. Miyajima H. Serizawa M. Macgillivray R.T. Gitlin J.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 2539-2543Crossref PubMed Scopus (508) Google Scholar, 11Morita H. Ikeda S. Yamamoto K. Morita S. Yoshida K. Nomoto S. Kato M. Yanagisawa N. Ann. Neurol. 1995; 37: 646-656Crossref PubMed Scopus (229) Google Scholar, 12Yoshida K. Furihata K. Takeda S. Nakamura A. Yamamoto K. Morita H. Hiyamuta S. Ikeda S. Shimuzu N. Yanagisawa N. Nat. Genet. 1995; 9: 267-272Crossref PubMed Scopus (421) Google Scholar, 13Harris Z.L. Migas M.C. Hughes A.E. Logan J.I. Gitlin J.D. Q. J. Med. 1996; 89: 355-359Crossref Scopus (39) Google Scholar, 14Okamoto N. Wada S. Oga T. Kawabata Y. Baba Y. Habu D. Takeda Z. Wada Y. Hum. Genet. 1996; 97: 755-758Crossref PubMed Scopus (95) Google Scholar, 15Takahashi Y. Miyajima H. Shirabe S. Nagataki S. Suenaga A. Gitlin J.D. Hum. Mol. Genet. 1996; 5: 81-84Crossref PubMed Scopus (106) Google Scholar). These individuals have very little or undetectable levels of ceruloplasmin and severe intracellular iron accumulation in a number of organs, including the brain, particularly in the deep extrapyramidal motor nuclei, where it is associated with neurodegeneration. The neurodegeneration is likely to be a consequence of oxidative stress induced by the oxidation of ferrous iron by agents such as hydrogen peroxide (1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar). In support of this, Miyajima et al. (16Miyajima H. Takahashi Y. Serizawa M. Kaneko E. Gitlin J.D. Free Radical Biol. Med. 1996; 20: 757-760Crossref PubMed Scopus (62) Google Scholar) reported a dramatic increase in the levels of lipid peroxidation in the plasma of individuals with aceruloplasminemia. A number of other neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Hallervorden-Spatz disease are also associated with altered brain iron metabolism and free radical injury (17Gerlach M. Ben-Shachar D. Riederer P. Youdim M.B.H. J. Neurochem. 1994; 63: 793-807Crossref PubMed Scopus (645) Google Scholar). It is therefore possible that ceruloplasmin might contribute to the pathology seen in these neurodegenerative diseases as well.Although generally considered a soluble plasma protein of hepatic origin, we now provide evidence using a monoclonal antibody, mAb 1The abbreviations used are: mAb, monoclonal antibody; GPI, glycosylphosphatidylinositol; PI-PLC, phosphatidylinositol-specific phospholipase C; DMEM, Dulbecco's modified Eagle's medium; PVDF, polyvinylidene difluoride; PAGE, polyacrylamide gel electrophoresis; TBSS, Tris-buffered saline solution; GFAP, glial fibrillary acidic protein. 1The abbreviations used are: mAb, monoclonal antibody; GPI, glycosylphosphatidylinositol; PI-PLC, phosphatidylinositol-specific phospholipase C; DMEM, Dulbecco's modified Eagle's medium; PVDF, polyvinylidene difluoride; PAGE, polyacrylamide gel electrophoresis; TBSS, Tris-buffered saline solution; GFAP, glial fibrillary acidic protein. 1A1, of a novel GPI-anchored form of ceruloplasmin that is localized to the surface of astrocytes in the central nervous system. The cell surface localization of ceruloplasmin is not seen on hepatocytes and cells of the choroid plexus, both of which are known to secrete ceruloplasmin. Since iron deposition occurs in the brain in aceruloplasminemia and because the level of the secreted form of ceruloplasmin in the cerebrospinal fluid is very low, this novel membrane-associated form of ceruloplasmin is likely to play an important role in iron metabolism in the central nervous system.DISCUSSIONWe provide evidence that the 135-kDa cell surface molecule recognized by the mAb 1A1, which is expressed exclusively by astrocytes in the rat central nervous system (18Mittal B. David S. Mol. Cell. Neurosci. 1994; 5: 63-77Crossref PubMed Scopus (8) Google Scholar, 32Mittal B. David S. Mol. Cell. Neurosci. 1994; 5: 78-86Crossref PubMed Scopus (12) Google Scholar), is a novel GPI-anchored form of ceruloplasmin. The molecule recognized by the mAb 1A1 was purified by immunoaffinity chromatography using detergent-solubilized membrane extracts of C6 glioma tumors or cultured C6 glioma cells that also express this molecule. N-terminal microsequence analysis of the immunoaffinity-purified 135-kDa band indicated that the molecule recognized by the mAb 1A1 is identical (or homologous) to ceruloplasmin, which is classically considered a plasma protein of hepatic origin. Two-dimensional gel electrophoresis revealed the presence of only one 135-kDa polypeptide in the immunoaffinity-purified material, suggesting that mAb 1A1 recognizes only one molecule, namely ceruloplasmin. Additional evidence that the molecule recognized by this monoclonal antibody is ceruloplasmin (or homologous to it) was provided by the following experiments. (i) Western blot analysis demonstrated that the mAb 1A1-purified protein is recognized by a polyclonal anti-ceruloplasmin antibody, (ii) the monoclonal antibody 1A1 immunoprecipitates a 135-kDa protein from rat serum, and (iii) no differences were observed in the peptide fragments generated by Cleveland mapping of ceruloplasmin from serum and that from membrane preparations of C6 glioma cells.We have also shown previously by metabolic labeling with [35S]methionine that this 135-kDa molecule is synthesized by astrocytes (18Mittal B. David S. Mol. Cell. Neurosci. 1994; 5: 63-77Crossref PubMed Scopus (8) Google Scholar). Immunofluorescence labeling of cells in vitro and iodination of cell surface proteins followed by immunoprecipitation showed that this molecule is associated with the plasma membrane (18Mittal B. David S. Mol. Cell. Neurosci. 1994; 5: 63-77Crossref PubMed Scopus (8) Google Scholar). In addition, as shown for ceruloplasmin synthesized by liver cells in vitro (28Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar), we have shown that there is only a small reduction in the molecular weight of this molecule when astrocyte cultures are treated with tunicamycin (18Mittal B. David S. Mol. Cell. Neurosci. 1994; 5: 63-77Crossref PubMed Scopus (8) Google Scholar), suggesting that it is poorly glycosylated. We have also reported previously that the 1A1 antigen, which we have shown here to be ceruloplasmin, increases in the cerebellum with postnatal development (32Mittal B. David S. Mol. Cell. Neurosci. 1994; 5: 78-86Crossref PubMed Scopus (12) Google Scholar). Several earlier studies have reported the presence of ceruloplasmin mRNA in the brain (33Thomas T. Schreiber G. Jaworowski A. Dev. Biol. 1989; 134: 38-47Crossref PubMed Scopus (69) Google Scholar, 34Gaitskhoki V.S. Voronina O.V. Denezhkina V.V. Pliss M.G. Puchkova L.V. Shvartsman A.L. Neifakh S.A. Biokhimiia. 1990; 55: 927-937PubMed Google Scholar, 35Shvartsman A.L. Voronina O.V. Gaitskoki V.S. Patkin E.L. Molekuliarnaia Biologiia. 1990; 24: 657-662Google Scholar, 36Yang F.M. Friedrichs W.E. Cupples R.L. Bonifacio M.J. Sanford J.A. Horton W.A. Bowman B.H. J. Biol. Chem. 1990; 265: 10780-10785Abstract Full Text PDF PubMed Google Scholar). More recently, Klompet al. (37Klomp L.W.J. Farhangrazi Z.S. Dugan L.L. Gitlin J.D. J. Clin. Invest. 1996; 98: 207-215Crossref PubMed Scopus (172) Google Scholar) have reported ceruloplasmin gene expression by astrocytes. We now provide evidence of a novel GPI-anchored form of ceruloplasmin expressed on the surface of astrocytes in the mammalian central nervous system and that it has oxidase activity.The cell surface localization of ceruloplasmin is unique to astrocytes, since cells of the choroid plexus and hepatocytes, both of which secrete ceruloplasmin, do not show surface labeling with mAb 1A1. Fibroblasts that form the fibroblastic capsule of various organs are the only other cell type to express this molecule on the cell surface (18Mittal B. David S. Mol. Cell. Neurosci. 1994; 5: 63-77Crossref PubMed Scopus (8) Google Scholar). This cell surface localization of ceruloplasmin cannot be the result of ceruloplasmin spanning the cell membrane, since it does not have a sufficiently long hydrophobic amino acid stretch that could serve as a membrane-spanning domain (27Aldred A.R. Grimes A. Schreiber G. Mercer J.F.B. J. Biol. Chem. 1987; 262: 2875-2878Abstract Full Text PDF PubMed Google Scholar, 28Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar). Our demonstration that the surface labeling with the monoclonal antibody can be removed by PI-PLC treatment shows that ceruloplasmin is anchored to the cell surface by a GPI anchor. Experiments in which immunoaffinity-purified ceruloplasmin, from PI-PLC cleaved material obtained from C6 glioma cells, was labeled on Western blots with an antibody that specifically recognizes the GPI anchor provide direct evidence that it is itself GPI-anchored to the cell surface. These results therefore provide the first evidence of a GPI-anchored form of ceruloplasmin.Interestingly, near the C-terminal end, plasma ceruloplasmin contains a potential site for GPI anchor attachment, consisting of small amino acids followed by a short hydrophobic sequence, that appears to satisfy the minimal requirement for a GPI anchor addition signal (29Ferguson M.A.J. Williams A.F. Annu. Rev. Biochem. 1988; 57: 285-320Crossref PubMed Scopus (947) Google Scholar, 30Englund P.T. Annu. Rev. Biochem. 1993; 62: 121-138Crossref PubMed Google Scholar, 31Udenfriend S. Kodukula K. Annu. Rev. Biochem. 1995; 64: 563-591Crossref PubMed Scopus (434) Google Scholar). GPI anchor addition would result in a protein with a molecular weight similar to the secreted form since the cleaved C-terminal sequence would be replaced with a GPI-anchor precursor of similar molecular weight (29Ferguson M.A.J. Williams A.F. Annu. Rev. Biochem. 1988; 57: 285-320Crossref PubMed Scopus (947) Google Scholar, 30Englund P.T. Annu. Rev. Biochem. 1993; 62: 121-138Crossref PubMed Google Scholar, 31Udenfriend S. Kodukula K. Annu. Rev. Biochem. 1995; 64: 563-591Crossref PubMed Scopus (434) Google Scholar). PIG-A, a gene that encodes a protein required to initiate GPI anchor assembly, is expressed at a much higher level in the brain than in other tissues (38Yu J. Medof M.E. Biochem. Biophys. Res. Commun. 1995; 215: 497-503Crossref PubMed Scopus (1) Google Scholar). Thus, astrocytes that are found in the brain may be able to initiate GPI anchor addition more readily than other cell types, such as hepatocytes. Alternatively, the GPI-anchored and secreted forms of ceruloplasmin might be generated through differential splicing, perhaps in a manner similar to the different isoforms of decay-accelerating factor (39Nonaka M. Miwa T. Okada N. Nonaka M. Okada H. J. Immunol. 1995; 155 (, 3048): 3037PubMed Google Scholar). Interestingly, Mollgard et al. (40Mollgard K. Dziegielewska K.M. Saunders N.R. Zakut H. Soreq H. Dev. Biol. 1988; 128: 207-221Crossref PubMed Scopus (101) Google Scholar) have reported that ceruloplasmin expressed by Xenopus oocytes following injection of mRNA from fetal human liver was secreted by the oocytes, whereas injection of mRNA from fetal human brain led to the expression of ceruloplasmin that was retained within the cells. Although these investigators did not localize the ceruloplasmin expressed from brain mRNA to a specific region of the cell, our studies suggest that it is likely to have been the membrane-bound GPI-anchored form of ceruloplasmin. Whether alternative splicing might be responsible for the different isoforms of ceruloplasmin cannot be determined based on the genomic sequence of ceruloplasmin, since it has not yet been fully characterized, and at present, consists only of the exons and intron/exon boundaries of the human liver cDNA (41Daimon M. Yamatani K. Igarashi M. Fukase N. Kawanami T. Kato T. Tominaga M. Sasaki H. Biochem. Biophys. Res. Commun. 1995; 208: 1028-1035Crossref PubMed Scopus (40) Google Scholar).An important finding is the evidence that the GPI-anchored form of ceruloplasmin has oxidase activity. This finding suggests that this unique form of ceruloplasmin on the surface of astrocytes in the central nervous system is likely to play a role in iron metabolism (1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar,3Kaplan J. O'Halloran T.V. Science. 1996; 271: 1510-1512Crossref PubMed Scopus (124) Google Scholar, 26Osaki S. Johnson D.A. Frieden E. J. Biol. Chem. 1966; 241: 2746-2751Abstract Full Text PDF PubMed Google Scholar) and antioxidant defense (42Gutteridge J.M.C. FEBS Lett. 1983; 157: 37-40Crossref PubMed Scopus (129) Google Scholar, 43Gutteridge J.M.C. Quinlan G.J. Biochim. Biophys. Acta. 1993; 1156: 144-150Crossref PubMed Scopus (93) Google Scholar). Convincing evidence for a role for this form of ceruloplasmin in iron metabolism comes from studies of individuals with hereditary ceruloplasmin deficiency in which there is marked deposition of iron in various organs including the brain (8Miyajima H. Nishimura Y. Mizoguchi K. Sakamoto M. Shimizu T. Honda N. Neurology. 1987; 37: 761-767Crossref PubMed Google Scholar, 9Logan J.I. Harveyson K.B. Wisdom G.B. Hughes A.E. Archbold G.P.R. Q. J. Med. 1994; 87: 663-670Google Scholar, 10Harris Z.L. Takahashi Y. Miyajima H. Serizawa M. Macgillivray R.T. Gitlin J.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 2539-2543Crossref PubMed Scopus (508) Google Scholar, 11Morita H. Ikeda S. Yamamoto K. Morita S. Yoshida K. Nomoto S. Kato M. Yanagisawa N. Ann. Neurol. 1995; 37: 646-656Crossref PubMed Scopus (229) Google Scholar, 12Yoshida K. Furihata K. Takeda S. Nakamura A. Yamamoto K. Morita H. Hiyamuta S. Ikeda S. Shimuzu N. Yanagisawa N. Nat. Genet. 1995; 9: 267-272Crossref PubMed Scopus (421) Google Scholar, 13Harris Z.L. Migas M.C. Hughes A.E. Logan J.I. Gitlin J.D. Q. J. Med. 1996; 89: 355-359Crossref Scopus (39) Google Scholar, 14Okamoto N. Wada S. Oga T. Kawabata Y. Baba Y. Habu D. Takeda Z. Wada Y. Hum. Genet. 1996; 97: 755-758Crossref PubMed Scopus (95) Google Scholar, 15Takahashi Y. Miyajima H. Shirabe S. Nagataki S. Suenaga A. Gitlin J.D. Hum. Mol. Genet. 1996; 5: 81-84Crossref PubMed Scopus (106) Google Scholar). Since there is no evidence that ceruloplasmin from plasma crosses the blood-brain barrier, and the levels of the secreted form of ceruloplasmin in the cerebrospinal fluid is normally very low (1 μg/ml; Ref. 44Del Principe D. Menichelli A. Colistra C. Acta Paediatr. Scand. 1989; 78: 327-328Crossref PubMed Google Scholar), the GPI-anchored form of ceruloplasmin on astrocytes, which comprise 25% of the total volume of the brain (45Pope A. Schoffeniels E. Franck G. Hertz L. Tower D.B. Dynamic Properties of Glial Cells. Pergamon Press, Oxford1977: 13-20Google Scholar), is likely to be the major form of ceruloplasmin in the central nervous system. This GPI-anchored form of ceruloplasmin is similar to a recently identified ferroxidase in yeast called Fet3 (4Askwith C. Eide D. Van Ho A. Bernard P.S. Li L. Davis Kaplan S. Sipe D.M. Kaplan J. Cell. 1994; 76: 403-410Abstract Full Text PDF PubMed Scopus (582) Google Scholar, 5De Silva D.M. Askwith C.C. Eide D. Kaplan J. J. Biol. Chem. 1995; 270: 1098-1101Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). Fet3, like ceruloplasmin, is a copper-binding ferroxidase. In addition, Fet3 is also attached to the cell surface, but unlike the GPI-anchored form of ceruloplasmin, it has a single transmembrane domain and has a molecular mass of 72 kDa (4Askwith C. Eide D. Van Ho A. Bernard P.S. Li L. Davis Kaplan S. Sipe D.M. Kaplan J. Cell. 1994; 76: 403-410Abstract Full Text PDF PubMed Scopus (582) Google Scholar, 5De Silva D.M. Askwith C.C. Eide D. Kaplan J. J. Biol. Chem. 1995; 270: 1098-1101Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). Interestingly, recent studies show that Fet3 ferroxidase activity is required for iron transport into the cell via a newly described iron transporter called Ftr1 (6Stearman R. Yuan D.S. Yamaguchi-Iwai Y. Klausner R.D. Dancis A. Science. 1996; 271: 1552-1557Crossref PubMed Scopus (574) Google Scholar). Whether the GPI-anchored form of ceruloplasmin in the mammalian central nervous system also functions along with a transporter similar to Ftr1 to transport ferric (Fe(III)) iron from the extracellular compartment into astrocytes is not known at present. Such a mechanism may contribute, along with other non-transferrin uptake systems (1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar, 7Sturrock A. Alexander J. Lamb J. Craven C.M. Kaplan J. J. Biol. Chem. 1990; 265: 3139-3145Abstract Full Text PDF PubMed Google Scholar), to the influx of iron into astrocytes, which lack both the transferrin receptor (46Giometto B. Bozza F. Argentiero V. Gallo P. Pagni S. Piccinno M.G. Tavolato B. J. Neurol. Sci. 1990; 98: 81-90Abstract Full Text PDF PubMed Scopus (82) Google Scholar,47Roskams A.J. Connor J.R. J. Neurosci. Res. 1990; 31: 421-427Crossref Scopus (34) Google Scholar) and melanotransferrin (48Rothenberger S. Food M.R. Gabathuler R. Kennard M.L. Yamada T. Yasuhara O. McGeer P.L. Jefferies W.A. Brain Res. 1996; 712: 117-121Crossref PubMed Scopus (87) Google Scholar). It is also possible that the egress of ferrous (Fe(II)) iron from neurons, oligodendrocytes, and astrocytes may occur via some as yet unidentified transporter, such as that proposed for other mammalian cells (3Kaplan J. O'Halloran T.V. Science. 1996; 271: 1510-1512Crossref PubMed Scopus (124) Google Scholar). The Fe(II) iron exiting these cells could become oxidized by the GPI-anchored form of ceruloplasmin on the surface of astrocytes. Since astrocyte processes are distributed throughout the central nervous system, ceruloplasmin located on astrocytes is ideally positioned to effectively oxidize the highly toxic ferrous iron to the ferric form. The latter may then be available for reutilization or cleared from the central nervous system by binding to transferrin or melanotransferrin.Besides aceruloplasminemia, iron deposition has been observed in the substantia nigra in Parkinson's disease (49Hirsch E.C. Brandel J.-P. Galle P. Javoy-Agid F. Agid Y. J. Neurochem. 1991; 56: 446-451Crossref PubMed Scopus (442) Google Scholar, 50Sofic E. Paulus W. Jellinger K. Riederer P. Youdim M.B.H. J. Neurochem. 1991; 56: 978-982Crossref PubMed Scopus (449) Google Scholar), in the cortex and amyloid plaques in Alzheimer's disease (51Connor J.R. Snyder B.S. Beard J.L. Fine R.E. Mufson E.J. J. Neurosci. Res. 1992; 31: 327-335Crossref PubMed Scopus (318) Google Scholar, 52Good P.F. Perl D.P. Bierer L. Schmeidler J. Ann. Neurol. 1992; 31: 286-292Crossref PubMed Scopus (427) Google Scholar), in amyotrophic lateral sclerosis (53Oba H. Araki T. Ohtomo K. Monzawa S. Uchiyama G. Koizumi K. Nogata Y. Kachi K. Shiozawa Z. Kobayashi M. 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Neurochem. 1989; 52: 381-389Crossref PubMed Scopus (1211) Google Scholar, 58Dexter D.T. Holley A.E. Flitter W.D. Slater T.F. Wells F.R. Daniel S.E. Lees A.J. Jenner P. Marsden C.D. Movement Disorders. 1994; 9: 92-97Crossref PubMed Scopus (383) Google Scholar, 59Lovell M.A. Ehmann E.D. Butler S.M. Markesbery W.R. Neurology. 1995; 45: 1594-1601Crossref PubMed Scopus (560) Google Scholar, 60Zhou Y. Richardson J.S. Mombourquette M.J. Weil J.A. Neurosci. Lett. 1995; 195: 89-92Crossref PubMed Scopus (47) Google Scholar). Reduction in ceruloplasmin has been reported in the cortex of patients with Alzheimer's disease (61Connor J.R. Tucker P. Johnson M. Snyder B. Neurosci. Lett. 1993; 159: 88-90Crossref PubMed Scopus (92) Google Scholar). It is possible that damage to astrocytes, resulting in reduced levels of the GPI-anchored form of ceruloplasmin in the affected gray matter regions, might lead to the iron deposition and free radical generation that causes the neuronal degeneration seen in these diseases. This is further supported by the finding that the ferroxidase activity of ceruloplasmin has been shown to inhibit ferrous iron-catalyzed phospholipid peroxidation in vitro (42Gutteridge J.M.C. FEBS Lett. 1983; 157: 37-40Crossref PubMed Scopus (129) Google Scholar, 43Gutteridge J.M.C. Quinlan G.J. Biochim. Biophys. Acta. 1993; 1156: 144-150Crossref PubMed Scopus (93) Google Scholar,62Samokyszyn V.M. Miller D.M. Reif D.W. Aust S.D. J. Biol. Chem. 1989; 264: 21-26Abstract Full Text PDF PubMed Google Scholar, 63De Silva D.M. Aust S.D. Can. J. Physiol. Pharmacol. 1993; 71: 715-720Crossref PubMed Scopus (64) Google Scholar). The GPI-anchored form of ceruloplasmin on astrocytes which has this important ferroxidase activity may regulate iron transport in and out of neurons and glia in the central nervous system, and may help limit lipid peroxidation in a tissue that is highly susceptible to oxidative injury. Iron plays an important role as a cofactor for various enzymes, such as the cytochromes of the electron transport chain and ribonucleotide reductase. On the other hand, free iron can generate highly toxic free radicals because it is a redox-active transition metal (1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar). A number of enzymes, binding proteins, and transporters have been identified that are involved in mobilizing, transporting, and sequestering iron (1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar, 2Jefferies W.A. Gabathuler R. Rothenberger S. Food M. Kennard M.L. Trends Cell Biol. 1996; 6: 223-228Abstract Full Text PDF PubMed Scopus (20) Google Scholar, 3Kaplan J. O'Halloran T.V. Science. 1996; 271: 1510-1512Crossref PubMed Scopus (124) Google Scholar). Recent studies on the yeastSaccharomyces cerevisiae have resulted in the identification of several proteins, such as Fet3 and Ftr1, which directly participate in iron transport in this organism (4Askwith C. Eide D. Van Ho A. Bernard P.S. Li L. Davis Kaplan S. Sipe D.M. Kaplan J. Cell. 1994; 76: 403-410Abstract Full Text PDF PubMed Scopus (582) Google Scholar, 5De Silva D.M. Askwith C.C. Eide D. Kaplan J. J. Biol. Chem. 1995; 270: 1098-1101Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 6Stearman R. Yuan D.S. Yamaguchi-Iwai Y. Klausner R.D. Dancis A. Science. 1996; 271: 1552-1557Crossref PubMed Scopus (574) Google Scholar). The mammalian homologues of many of these proteins have yet to be identified. Ceruloplasmin, the major ferroxidase of plasma (300–450 μg/ml), is required for iron transport by transferrin. The oxidation of ferrous iron (Fe(II)) to ferric iron (Fe(III)) mediated by ceruloplasmin is necessary for iron incorporation into transferrin, since transferrin only binds the ferric form of iron. As a ferroxidase, ceruloplasmin might also play a role in a transferrin-independent iron uptake system, such as the one identified by Kaplan and colleagues (7Sturrock A. Alexander J. Lamb J. Craven C.M. Kaplan J. J. Biol. Chem. 1990; 265: 3139-3145Abstract Full Text PDF PubMed Google Scholar), which requires reduction of iron at the cell surface (reviewed in Ref. 1De Silva D.M. Askwith C.C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (155) Google Scholar). Direct evidence for the role of ceruloplasmin in iron metabolism comes from studies of individuals with aceruloplasminemia, a hereditary deficiency of ceruloplasmin (8Miyajima H" @default.
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• W2036545911 title "A Novel Glycosylphosphatidylinositol-anchored Form of Ceruloplasmin Is Expressed by Mammalian Astrocytes" @default.
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