A Novel Glycosylphosphatidylinositol-anchored Form of Ceruloplasmin Is Expressed by Mammalian Astrocytes

Bharatkumar N Patel,Samuel David

doi:10.1074/jbc.272.32.20185

Bharatkumar N Patel, Samuel David

Open Access

https://doi.org/10.1074/jbc.272.32.20185

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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.

Highlights

Iron plays an important role as a cofactor for various enzymes, such as the cytochromes of the electron transport chain and ribonucleotide reductase
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
We 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 [18, 32], is a novel GPI-anchored form of ceruloplasmin

Summary

Introduction

Iron plays an important role as a cofactor for various enzymes, such as the cytochromes of the electron transport chain and ribonucleotide reductase. Generally considered a soluble plasma protein of hepatic origin, we provide evidence using a monoclonal antibody, mAb1 1A1, of a novel GPI-anchored form of ceruloplasmin that is localized to the surface of astrocytes in the central nervous system.

Results

Conclusion