ReviewRethinking the role of ceruloplasmin in brain iron metabolism
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.
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