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

Ceruloplasmin is a copper containing ferroxidase that is essential for norm al iron homeostasis. Whereas ceruloplasmin in plasma is produced and secret ed by hepatocytes, in the brain a glycosylphosphatidylinositol (GPI)-anchor ed form of ceruloplasmin is expressed on the surface of astrocytes, By usin g a cDNA cloning approach, we have now determined that the GPI-anchored for m of ceruloplasmin is generated by alternative RNA splicing. The splicing o ccurs downstream of exon 18 and replaces the C-terminal 5 amino acids of th e secreted form with an alternative 30 amino acids that signal GPI anchor a ddition. RNase protection analysis demonstrates that the GPI-anchored form is the major form in the brain, whereas the secreted form predominates in t he liver. Individuals with aceruloplasminemia, a hereditary deficiency of c eruloplasmin, 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.