Review
Rethinking the role of ceruloplasmin in brain iron metabolism

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Abstract

For more than three decades, it has been widely accepted that ceruloplasmin plays an important role in iron efflux from mammalian cells, including brain cells, via the activity of ferroxidase. However, in light of recent findings, this view might not be completely accurate and the role of ceruloplasmin in brain iron metabolism may need to be re-evaluated. Based on recent studies, we propose in this article that the role of ceruloplasmin in iron uptake by brain neuronal cells might be more important than its role in iron release from the cells. A possible explanation of why the absence of ceruloplasmin induces excessive iron accumulation in neurons in aceruloplasminemia (ceruloplasmin gene mutations) was also discussed.

Section snippets

Ceruloplasmin in the brain

Ceruloplasmin (CP, or the sky-blue protein) was first isolated from pig serum by Holmberg and Laurell in 1948 [18]. It is an abundant serum alpha-2 glycoprotein and has a molecular mass of approximately 132 kDa. The CP polypeptide gene is on chromosome 3q25. This protein consists of a single polypeptide chain of 1046 amino acid residues and belongs to a family of multi-nuclear ‘blue’ copper oxidases which includes ascorbate oxidase and laccase. The X-ray structure of human serum ceruloplasmin

Ceruloplasmin plays a role in iron release from as well as uptake by brain neuronal cells

For over 30 years, CP has been postulated as the critical ferroxidase. Based on the observation that the ferroxidase activity of CP promoted iron incorporation into transferrin, a role for CP in iron efflux was first suggested by Oskai et al. in 1966 [30]. A recent study using an animal model of aceruloplasminemia [17] supports this possibility. However, despite years of investigation, the functions of brain CP (glycosylphosphatidylinositol-anchored and soluble CPs) in brain iron metabolism

Why the absence of ceruloplasmin leads to excessive iron accumulation in neuronal cells in aceruloplasminemia

If it is true that CP has a role in iron uptake, the question that needs to be answered is why the absent expression of CP can induce excessive iron accumulation in neurons and some other brain cells, as found in patients with aceruloplasminemia. The most acceptable answer found in the literature is that iron cannot be released from cells because of the absence of CP [11], [16], [20], [33], [42], [45]. Obviously, this is not a complete answer. If excessive iron accumulation in neuronal cells

Summary

Due to the well-established importance of CP in brain iron metabolism and the possible role of CP disregulation in neurodegeneration [12], [29], [33], [34], [39], a complete understanding of the role of CP in the brain is critical. Further investigation of the possibility described above is absolutely needed. In addition, two new proteins, ferroportin 1 [9] and hephaestin [44], required for exporting iron from enterocytes into the blood stream have been recently identified. It has been also

Acknowledgements

The studies in this laboratory were supported by Competitive Earmarked Grants of The Hong Kong Research Grants Council and The Hong Kong Polytechnic University Research Grants.

References (48)

  • B.N. Patel et al.

    Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain

    J. Biol. Chem.

    (2000)
  • Z.M. Qian et al.

    Expression of iron transport proteins and excessive iron accumulation of iron in the brain in neurodegenerative disorders

    Brain Res. Rev.

    (1998)
  • Z.M. Qian et al.

    Brain iron transport and neurondegeneration

    Trend. Mol. Med.

    (2001)
  • C.A. Reilly et al.

    Stimulation of the ferroxidase activity of ceruloplasmin during iron loading into ferritin

    Arch. Biochem. Biophys.

    (1997)
  • D.R. Richardson

    Role of ceruloplasmin and ascorbate in cellular iron release

    J. Lab. Clin. Med.

    (1999)
  • L.M. Sayre et al.

    Redox metals and neurodegeneratiove disease

    Curr. Opin. Chem. Biol.

    (1999)
  • J. Swain et al.

    Prooxidant iron and copper, with ferroxidase and xanthine oxidase activities in human atherosclerotic material

    FEBS Lett.

    (1995)
  • M.E. Van Eden et al.

    Intact human ceruloplasmin is required for the incorporation of iron into human ferritin

    Arch. Biochem. Biophys.

    (2000)
  • S.P. Young et al.

    Ceruloplasmin, transferrin and apotransferrin facilitate iron release from human liver cells

    FEBS Lett.

    (1997)
  • M.W.B. Bradbury

    Transport of iron in the blood–brain–cerebrospinal fluid system

    J. Neurochem.

    (1997)
  • M. Cellier et al.

    Nramp defines a family of membrane proteins

    Proc. Natl. Acad. Sci. U.S.A.

    (1995)
  • M.K. Cha et al.

    Ceruloplasmin has a distinct active site for the catalyzing glutathione-dependent reduction of alkyl hydroperoxide

    Biochemistry

    (1999)
  • A. Dancis et al.

    Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport

    Cell

    (1994)
  • A. Donovan et al.

    Positional cloning of zebrafish ferroportin 1 identifies a conserved vertebrate iron exporter

    Nature

    (2000)
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