Aceruloplasminemia

Satoshi      Kono

Abstract

Ceruloplasmin contains 95% of the copper in human serum and plays an important role in iron efflux from mammalian cells, including brain cells, due to the activity of ferroxidase, which oxidizes ferrous iron following its transfer to the cell surface via the iron transporter, ferroportin, and delivers ferric iron to extracellular transferrin. In the central nervous system, a glycosylphosphatidylinositol (GPI)-anchored ceruloplasmin bound to the cell membranes of astrocytes was found to be the major isoform of this protein. Inherited loss of the protein causes aceruloplasminemia, which is an autosomal recessive disorder characterized by progressive neurodegeneration of the retina and basal ganglia associated with specific inherited mutations in the ceruloplasmin gene. Aceruloplasminemia is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA) due to genetic defects associated with iron metabolism. Clinical and pathologic studies in patients with aceruloplasminemia and ceruloplasmin knockout mice revealed increased lipid peroxidation due to iron-mediated cellular radical injury which is caused by a marked accumulation of iron in the affected parenchymal tissues such as the retina, liver, pancreas and brain. In the following review of aceruloplasminemia, the ceruloplasmin gene expression, structure and function will be presented, and the role of ceruloplasmin in iron metabolism will be discussed. The pathogenesis of aceruloplasminemia provides valuable insights into the mechanisms regulating iron homeostasis and also identified models that can be used to further dissect the role of this metal in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, in which iron is accumulated.

Keywords: Ceruloplasmin, ferroxoidase, iron, mutation, neurodegeneration of brain iron accumulation (NBIA), pathology, radical injury, ferroportin, glycosylphosphatidylinositol (GPI)