Alternative RNA Splicing Generates a Glycosylphosphatidylinositol-anchored Form of Ceruloplasmin in Mammalian Brain

Ceruloplasmin is a copper-containing ferroxidase that is essential for normal iron homeostasis. Whereas ceruloplasmin in plasma is produced and secreted by hepatocytes, in the brain a glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is expressed on the surface of astrocytes. By using a cDNA cloning approach, we have now determined that the GPI-anchored form of ceruloplasmin is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the C-terminal 5 amino acids of the secreted form with an alternative 30 amino acids that signal GPI anchor addition. RNase protection analysis demonstrates that the GPI-anchored form is the major form in the brain, whereas the secreted form predominates in the liver. Individuals with aceruloplasminemia, a hereditary deficiency of ceruloplasmin, have severe iron deposition in a number of organs, including the brain where it results in neurodegeneration. Therefore, this novel GPI-anchored form of ceruloplasmin is likely to play an important role in iron metabolism in the central nervous system. Ceruloplasmin is a copper-containing ferroxidase that is essential for normal iron homeostasis. Whereas ceruloplasmin in plasma is produced and secreted by hepatocytes, in the brain a glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is expressed on the surface of astrocytes. By using a cDNA cloning approach, we have now determined that the GPI-anchored form of ceruloplasmin is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the C-terminal 5 amino acids of the secreted form with an alternative 30 amino acids that signal GPI anchor addition. RNase protection analysis demonstrates that the GPI-anchored form is the major form in the brain, whereas the secreted form predominates in the liver. Individuals with aceruloplasminemia, a hereditary deficiency of ceruloplasmin, have severe iron deposition in a number of organs, including the brain where it results in neurodegeneration. Therefore, this novel GPI-anchored form of ceruloplasmin is likely to play an important role in iron metabolism in the central nervous system. central nervous system glycosylphosphatidylinositol open reading frame human embryonic kidney 293T monoclonal antibody phosphatidylinositol-specific phospholipase C reverse transcriptase-polymerase chain reaction nucleotide kilobase pair Iron plays an important role in many biological processes. It is an essential cofactor for a variety of enzymes, including ribonucleotide reductase and aconitase, and its presence in heme imparts the ability of hemoglobin to transport oxygen and the ability of cytochrome oxidase to reduce oxygen to water. However, free iron is highly toxic because of its ability to generate free radicals. Ferrous (Fe(II)) iron can generate the highly reactive superoxide and hydroxyl radicals in the presence of molecular oxygen (1.Gutteridge J. Ann. Neurol. 1992; 32: S16-S21Crossref PubMed Scopus (160) Google Scholar). Consequently, iron metabolism is tightly regulated, and a variety of proteins have evolved to bind, transport, and sequester iron (2.De Silva D. Askwith C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (156) Google Scholar). Transferrin, the major iron transport protein in plasma, transports iron from sites of storage, such as the liver, to tissues utilizing iron. Ceruloplasmin, the major ferroxidase in plasma (300–400 μg/ml), promotes iron incorporation into transferrin as transferrin only binds ferric (Fe(III)) iron (3.Osaki S. Johnson D. Frieden E. J. Biol. Chem. 1966; 241: 2746-2751Abstract Full Text PDF PubMed Google Scholar). Direct evidence for a role of ceruloplasmin in iron metabolism in vivo is provided by studies of patients with aceruloplasminemia, a hereditary deficiency of ceruloplasmin due to null mutations in the ceruloplasmin gene (4.Miyajima H. Nishimura Y. Mizoguchi K. Sakamoto M. Shimizu T. Honda N. Neurology. 1987; 37: 761-767Crossref PubMed Google Scholar, 5.Harris Z. Takahashi Y. Miyajima H. Serizawa M. MacGillivray R. Gitlin J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 2539-2543Crossref PubMed Scopus (515) Google Scholar, 6.Yoshida K. Furihata K. Takeda S. Nakamura A. Yamamoto K. Morita H. Hiyamuta S. Ikeda S. Shimizu N. Yanagisawa N. Nat. Genet. 1995; 9: 267-272Crossref PubMed Scopus (426) Google Scholar). These patients have severe iron deposition in a variety of organs, including the brain where it results in neurodegeneration. The neurodegeneration appears to be due to an increased generation of free radicals by the accumulated iron. Indeed, there is a dramatic increase in the levels of lipid peroxidation products in the cerebrospinal fluid of patients with aceruloplasminemia (7.Miyajima H. Fujimoto M. Kohno S. Kaneko E. Gitlin J. Neurology. 1998; 51: 1188-1190Crossref PubMed Scopus (40) Google Scholar). A number of other neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Hallervorden-Spatz disease are also associated with abnormal iron deposition and free radical injury in the central nervous system (CNS)1 (8.Gerlach M. Ben-Shachar D. Riederer P. Youdim M. J. Neurochem. 1994; 63: 793-807Crossref PubMed Scopus (655) Google Scholar). Although ceruloplasmin is generally considered a plasma protein secreted by the liver, we recently demonstrated that a membrane-bound glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin is localized to the surface of astrocytes in the CNS (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). Hepatocytes, which produce the ceruloplasmin present in serum, do not express the GPI-anchored form. The transcript coding for serum ceruloplasmin has been cloned from human (10.Koschinsky M.L. Funk W.D. van Oost B.A. MacGillivray R.T. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 5086-5090Crossref PubMed Scopus (107) Google Scholar), rat (11.Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar), and mouse (12.Klomp L.W. Farhangrazi Z.D. Dugan L.L. Giltin J.D. J. Clin. Invest. 1996; 98: 207-215Crossref PubMed Scopus (175) Google Scholar) liver cDNA libraries, and only a single gene has been identified (13.Royle N. Irwin D. Koschinsky M. MacGillivray R. Hamerton J. Somatic Cell Mol. Genet. 1987; 13: 285-292Crossref PubMed Scopus (94) Google Scholar). This report describes the cloning and expression of a novel alternatively spliced transcript for the GPI-anchored form of ceruloplasmin. We also demonstrate that, in contrast to the liver which expresses mainly the secreted form, the brain expresses primarily the GPI-anchored form of ceruloplasmin. Since a lack of ceruloplasmin leads to excessive iron deposition in the brain and neurodegeneration, the GPI-anchored form of ceruloplasmin likely plays a crucial role in iron metabolism in the CNS. In order to screen the cDNA library, a probe proximal to the 3′ end of the open reading frame (ORF) of the rat serum ceruloplasmin transcript was generated by RT-PCR using primers based on published sequence (Ref. 11.Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar; GenBankTM accession number, L33869). The primers were FP1 (forward primer), 5′-GCA TGC TCG GTC CAC TGA TTC-3′, and RP1 (reverse primer), 5′-AAC ATT TTC CCA TTG ATA GCA T-3′. These primers amplify a 481-base pair product corresponding to nucleotides 2399–2879 of the ORF of the rat serum ceruloplasmin transcript. The probe was used to screen an oligo(dT)-primed rat C6 glioma cDNA library prepared by D. Feinstein (Cornell University). The library was made in Lambda Zap II using the EcoRI-XhoI directional cloning procedure and contained an original complexity of 1 × 106 clones. 3 × 105 clones were screened according to Sambrook et al. (14.Sambrook J. Fritsch E.F. Maniatis T. Molecular Cloning: A Laboratory Manual. 2nd Ed. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1989: 9.31-9.55Google Scholar). Twenty positive clones were obtained and were purified by two subsequent rounds of screening with the same probe. Two of the largest cDNA inserts were sequenced by automated fluorescence sequencing (Bio S&T). The complete sequences were aligned with the published sequence for rat serum ceruloplasmin (11.Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar) using the program MegAlign (DNASTAR). Full-length cDNA clones were generated by RT-PCR using the Perkin-Elmer XL PCR kit according to the manufacturer's instructions. The cDNA for the GPI-anchored form of ceruloplasmin was amplified from C6 glioma RNA using the following primers: CFP1 (common forward primer), 5′-GAC CTC GAG ATC GCG GGC TCC AAG AGG-3′, and GPIRP1 (GPI reverse primer), 5′- GAC GGA TCC ATT TAA ATA TGG CGT GAT AGC ACA-3′. The cDNA for the secreted (serum) form of ceruloplasmin was amplified from rat liver RNA using the following primers: CFP1 and SRP1 (serum reverse primer), 5′-GAC GGA TCC TTC ATC TGT CCA TCG GCA TTA CC-3′. To generate the expression construct, the PCR products were subcloned into the mammalian expression vector pEUK-C1 (CLONTECH). For the transfections, human embryonic kidney 293T (HEK 293T) cells were grown in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, vitamins, and penicillin/streptomycin (Life Technologies, Inc.) on in were using the system The medium was following the and was the following on cells grown on the the same the cells and were from the for and was on cells grown on using a monoclonal antibody to ceruloplasmin B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar) and with a antibody to as (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). For cells with the cDNA for GPI-anchored ceruloplasmin were with phosphatidylinositol-specific phospholipase C in were with (Life Technologies, Inc.) containing 5 and in 1 × 106 cells were in a of containing 5 Molecular and for cells were were by for and with the cells were as in containing and 1 μg/ml), to and of the as as the were with purified for and of protein A were and for were with containing with and the were and was as (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar), using a antibody The ceruloplasmin probe for the RNase protection was generated by RT-PCR using rat brain The primers used were (GPI forward primer), TGT GAT GGC and (GPI reverse primer), GGA TGG TGG TGA TGG These primers amplify a product of from the transcript for the GPI-anchored form of ceruloplasmin, corresponding to nucleotides of the The product was subcloned into and sequenced using the kit and the automated The RNase protection was as D. J. Neurol. 1997; PubMed Scopus Google Scholar). The containing the ceruloplasmin was with and using RNA RNA using to the probe. The probe was and 1 × 106 with of RNA from rat liver, C6 glioma rat brain, rat brain in The were with of RNase RNase A and RNase for 30 by of were and by on a This probe a for the GPI-anchored form of ceruloplasmin and a for the secreted form. The rat probe a The of the were using an RNA generated by of that the GPI-anchored form and the secreted (serum) form of ceruloplasmin were highly that only in the C (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). In order to the alternatively spliced transcript for the GPI-anchored form of ceruloplasmin, an oligo(dT)-primed C6 glioma cDNA library was screened with a probe proximal to the end of the ORF for the secreted form of rat ceruloplasmin (11.Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar). Twenty clones were obtained with that from 1 to sequences for two of the clones of and were aligned with the cDNA sequence for the secreted form of rat ceruloplasmin (11.Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar). This analysis that clones a novel transcript that was to that for secreted ceruloplasmin for a of the ORF as as the The largest cDNA contained the complete ORF for this alternatively spliced form of ceruloplasmin as as nucleotides of and nucleotides of A with the of human serum ceruloplasmin M. K. M. N. T. T. M. H. 1995; PubMed Scopus Google Scholar) that the novel cDNA from the cDNA for the secreted form downstream of exon 18 of the This alternatively spliced transcript a protein of amino acids with amino acids for secreted ceruloplasmin. The the of amino are and amino The ORF of the novel cDNA the C-terminal 5 amino acids of secreted ceruloplasmin with 30 alternative amino The alternative of 30 amino acids is as it is for GPI-anchored with a of In this of amino acids also a for GPI anchor addition. GPI are to a amino the amino of the C-terminal signal with of the signal S. K. Rev. 1995; PubMed Scopus Google Scholar). The amino of the alternative the is a for the GPI anchor also amino acids following the amino which are the 1 and amino The following the are for it appears that this alternatively spliced ceruloplasmin with its alternative C-terminal the for GPI anchor addition. To demonstrate that the alternatively spliced transcript for the GPI-anchored form of ceruloplasmin, cDNA clones for the alternatively spliced form, as as the secreted form were generated by RT-PCR and subcloned into the pEUK-C1 mammalian expression These ceruloplasmin expression were into 293T cells and for expression by and with the novel cDNA demonstrated surface with a monoclonal antibody to rat ceruloplasmin and This monoclonal antibody is and only rat ceruloplasmin (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, David S. Mol. 1994; PubMed Scopus Google Scholar). In cells with the cDNA for secreted ceruloplasmin not surface with the monoclonal antibody to ceruloplasmin C and This lack of is to that of cells and The novel cDNA for a membrane-bound form of ceruloplasmin. To that of cells were ceruloplasmin, the and of the cells were with order to bovine ceruloplasmin present in fetal bovine and with a antibody to ceruloplasmin. The demonstrates that ceruloplasmin is associated with the cells with the cDNA for the alternatively spliced form of ceruloplasmin The of this protein of is to the of GPI-anchored ceruloplasmin purified from rat astrocytes C6 glioma cells (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). In ceruloplasmin is in the medium of cells with the cDNA for the secreted form This ceruloplasmin appears that produced by the cells with the novel cDNA transcript. The of the is with it as the GPI which is following of the C-terminal signal to the of GPI-anchored on the and lipid of the anchor S. K. Rev. 1995; PubMed Scopus Google Scholar). we to demonstrate that the ceruloplasmin expressed on the surface of the cells with the novel cDNA was in GPI-anchored and not by a protein To this the cells were with an that GPI from GPI-anchored proteins M. P. PubMed Scopus Google Scholar). This surface with the monoclonal antibody to ceruloplasmin A and with the same and surface and These evidence that the novel alternatively spliced transcript for the GPI-anchored form of ceruloplasmin. To the of the for GPI-anchored ceruloplasmin and secreted ceruloplasmin, RNase protection were on rat brain, liver, and C6 glioma using a probe that nucleotides of the cDNA for GPI-anchored ceruloplasmin. The probe is by the transcript for GPI-anchored ceruloplasmin to a of and it is by the transcript for secreted ceruloplasmin to a of and rat brain express the transcript for GPI-anchored ceruloplasmin a of the transcript for the secreted form is expressed in the is in expression and In rat liver expresses the transcript for secreted ceruloplasmin a of the transcript for the GPI-anchored form is also C6 glioma cells express the transcript for GPI-anchored ceruloplasmin, with levels of the secreted form. These results that whereas the liver the secreted form of ceruloplasmin, the brain the GPI-anchored form. The GPI-anchored form of ceruloplasmin was recently identified in using protein (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). By using a monoclonal antibody ceruloplasmin was to be expressed on the surface of astrocytes in the mammalian brain (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar) as as by cells and in a number of tissues including the liver David S. Mol. 1994; PubMed Scopus Google Scholar). However, hepatocytes, which produce the ceruloplasmin present in serum, do not express the GPI-anchored form. N. and S. studies that GPI-anchored ceruloplasmin and serum ceruloplasmin are highly that only in the C-terminal (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). The that two of ceruloplasmin be produced by alternative RNA splicing was by the of and K. K. N. H. H. Biol. PubMed Scopus Google Scholar). These demonstrated that ceruloplasmin expressed following of from fetal human liver was secreted by the whereas of from fetal human brain to the expression of ceruloplasmin that was by the We now that the GPI-anchored form of ceruloplasmin is generated by alternative RNA splicing and that it is the form in the The complete cDNA sequences for human (10.Koschinsky M.L. Funk W.D. van Oost B.A. MacGillivray R.T. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 5086-5090Crossref PubMed Scopus (107) Google Scholar), rat (11.Fleming R.E. Gitlin J.D. J. Biol. Chem. 1990; 265: 7701-7707Abstract Full Text PDF PubMed Google Scholar), and mouse (12.Klomp L.W. Farhangrazi Z.D. Dugan L.L. Giltin J.D. J. Clin. Invest. 1996; 98: 207-215Crossref PubMed Scopus (175) Google Scholar) serum ceruloplasmin have been and whereas the have been only for the human cDNA M. K. M. N. T. T. M. H. 1995; PubMed Scopus Google Scholar), the are likely to be in the rat and mouse due to the of sequence (12.Klomp L.W. Farhangrazi Z.D. Dugan L.L. Giltin J.D. J. Clin. Invest. 1996; 98: 207-215Crossref PubMed Scopus (175) Google Scholar). The novel transcript for ceruloplasmin from the transcript for secreted ceruloplasmin downstream of exon This alternative splicing leads to the of the 5 amino acids in secreted ceruloplasmin with an alternative 30 amino acids in the novel form. This alternative C-terminal is and a signal for GPI anchor S. K. Rev. 1995; PubMed Scopus Google Scholar). of the cDNA for the novel alternatively spliced form of ceruloplasmin into 293T cells that it for a form of ceruloplasmin. In cells with an that GPI from GPI-anchored the surface of ceruloplasmin. with the cDNA for the secreted form do not express ceruloplasmin on the surface in it into the that the novel alternatively spliced transcript in for the GPI-anchored form of ceruloplasmin. This form of ceruloplasmin is to ferroxidase as it the for the and the alternative C-terminal is to the of ceruloplasmin as the C of the secreted protein is the K. A. J. Biol. Chem. 1996; Scopus Google Scholar, P. E. K. J. Biol. Chem. 1997; Scopus Google Scholar). In with we have that GPI-anchored ceruloplasmin, from the surface of C6 glioma cells with oxidase (9.Patel B.N. David S. J. Biol. Chem. 1997; 272: 20185-20190Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). RNase protection on rat brain and liver, using a probe that for the GPI-anchored and secreted of ceruloplasmin, that the brain expresses the transcript for the GPI-anchored form. In liver expresses a of the transcript for the secreted form. This is with that the liver of ceruloplasmin for into the In the liver also a of the transcript for the GPI-anchored form that is likely to be expressed by ceruloplasmin from the not to the and levels of ceruloplasmin in the cerebrospinal fluid are 1 with in plasma J. A. M. T. P. R. R. PubMed Scopus Google Scholar), it that the GPI-anchored form, produced the brain, is the major form of ceruloplasmin in that have ceruloplasmin expression in the mammalian primarily by analysis using that alternatively spliced T. A. Biol. PubMed Scopus Google Scholar, M. A. S. 1990; Google Scholar, J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar). In ceruloplasmin has been localized to astrocytes and by K. K. N. H. H. Biol. PubMed Scopus Google Scholar). Gitlin and (12.Klomp L.W. Farhangrazi Z.D. Dugan L.L. Giltin J.D. J. Clin. Invest. 1996; 98: 207-215Crossref PubMed Scopus (175) Google Scholar, L.W. Gitlin J.D. Mol. Genet. 1996; PubMed Scopus (156) Google Scholar) have localized ceruloplasmin expression by in to of astrocytes in the with the expression in astrocytes the brain These and other (12.Klomp L.W. Farhangrazi Z.D. Dugan L.L. Giltin J.D. J. Clin. Invest. 1996; 98: 207-215Crossref PubMed Scopus (175) Google Scholar, L.W. Gitlin J.D. Mol. Genet. 1996; PubMed Scopus (156) Google Scholar, K. Invest. Sci. 1998; Google Scholar) have also ceruloplasmin expression in astrocytes and by in The we present in this that the ceruloplasmin in the CNS by is the GPI-anchored form. ceruloplasmin is alternatively spliced to produce the GPI-anchored form in the CNS is not However, it is that with proteins to the surface by a protein GPI-anchored which are in have a of lateral the lipid S. K. Rev. 1995; PubMed Scopus Google Scholar). In the GPI anchor has been identified as an signal for E. J. Cell Sci. Google Scholar). This of a localized of ceruloplasmin where for in the of and the of ceruloplasmin with other proteins in iron of GPI-anchored proteins is that can be from the plasma of to sites of S. D. M. H. 1995; PubMed Scopus Google Scholar). This cells that do not express GPI-anchored ceruloplasmin to the protein from astrocytes This be in ceruloplasmin has been localized to astrocytes and by K. K. N. H. H. Biol. PubMed Scopus Google Scholar) do not to express ceruloplasmin (12.Klomp L.W. Farhangrazi Z.D. Dugan L.L. Giltin J.D. J. Clin. Invest. 1996; 98: 207-215Crossref PubMed Scopus (175) Google Scholar, L.W. Gitlin J.D. Mol. Genet. 1996; PubMed Scopus (156) Google Scholar). The role of ceruloplasmin in vivo is demonstrated by studies of with aceruloplasminemia, a hereditary deficiency of ceruloplasmin. These patients severe and associated with iron deposition and neurodegeneration in a number of brain including the and (4.Miyajima H. Nishimura Y. Mizoguchi K. Sakamoto M. Shimizu T. Honda N. Neurology. 1987; 37: 761-767Crossref PubMed Google Scholar, 5.Harris Z. Takahashi Y. Miyajima H. Serizawa M. MacGillivray R. Gitlin J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 2539-2543Crossref PubMed Scopus (515) Google Scholar, 6.Yoshida K. Furihata K. Takeda S. Nakamura A. Yamamoto K. Morita H. Hiyamuta S. Ikeda S. Shimizu N. Yanagisawa N. Nat. Genet. 1995; 9: 267-272Crossref PubMed Scopus (426) Google Scholar). The neurodegeneration is likely due to the generation of oxygen free radicals the Indeed, Miyajima et al. (7.Miyajima H. Fujimoto M. Kohno S. Kaneko E. Gitlin J. Neurology. 1998; 51: 1188-1190Crossref PubMed Scopus (40) Google Scholar) have a increase in lipid peroxidation products in the cerebrospinal fluid of patients with patients with the iron the of H. Takahashi Y. T. Shimizu H. N. Gitlin J.D. Ann. Neurol. 1997; PubMed Scopus Google Scholar). The iron deposition in the tissues of patients with aceruloplasminemia that the role of ceruloplasmin in vivo is to excessive iron Ceruloplasmin this by iron by iron and in that ceruloplasmin of A role for ceruloplasmin in iron was by and (3.Osaki S. Johnson D. Frieden E. J. Biol. Chem. 1966; 241: 2746-2751Abstract Full Text PDF PubMed Google Scholar), based on the that the ferroxidase of ceruloplasmin iron incorporation into Indeed, in with ceruloplasmin has been to iron from cells in S. M. S. 1997; PubMed Scopus Google Scholar). A role for ceruloplasmin in iron from cells is also by the of a ceruloplasmin which is expressed by the and which is for the of iron of cells Askwith C. N. J. Nat. Genet. PubMed Scopus Google Scholar). for are to iron from the where it and the have severe which is to ceruloplasmin and to ferroxidase is a protein that appears to be localized to the surface of is to with an iron transport protein to the of iron of The GPI-anchored form of ceruloplasmin a iron from cells in the CNS. This of a ferroxidase with an iron transport protein has with an iron system in in which a surface is for iron by an iron transport C. D. A. S. Kaplan J. 1994; 76: Full Text PDF PubMed Scopus Google Scholar, R. D. Y. R. A. 1996; PubMed Scopus Google Scholar). However, the the of the GPI-anchored ceruloplasmin with an iron on mammalian cells to iron In to iron ceruloplasmin also iron by iron by a iron system that has been identified in (2.De Silva D. Askwith C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (156) Google Scholar). This system the of iron to iron the surface for to (2.De Silva D. Askwith C. Kaplan J. Physiol. Rev. 1996; 76: 31-47Crossref PubMed Scopus (156) Google Scholar). This iron system be important for cells that do not express the transferrin such as astrocytes A. J. J. 1990; Scopus Google Scholar). a ceruloplasmin this of iron the surface and by this system. Indeed, this is by the that ceruloplasmin iron by a iron system in D. P. 1995; PubMed Scopus Google Scholar). It is not the lack of GPI-anchored ceruloplasmin in the CNS is for the iron deposition and neurodegeneration in aceruloplasminemia this is a of the iron However, in the of iron hereditary severe iron deposition occurs in organs, including the liver, iron deposition not in the and are not 1998; Google Scholar). This that the lack of GPI-anchored ceruloplasmin in the CNS is likely to be primarily for the iron deposition and neurodegeneration in a in the of GPI-anchored ceruloplasmin in of the CNS to the in a variety of neurodegenerative in which excessive iron occurs to be We and for and We D. Feinstein and C. for the C6 glioma cDNA library and for on the

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