Ceruloplasmin in neurodegenerative diseases

Sarah J. Texel, Xueying Xu, Z. Leah Harris*

*Corresponding author for this work

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Two decades ago, patients lacking circulating serum ceruloplasmin (Cp) presented with neurodegeneration associated with brain iron accumulation. These patients, with mutations in the MCO (multi-copper oxidase), Cp, revealed an essential role for Cp in iron homoeostasis. The patientswere diagnosed in adulthood with CNS (central nervous system) disease and progressed rapidly, making understanding the mechanism of disease imperative. We now know that (i) Cp regulates the ef.ciency of iron efflux, (ii) Cp stabilizes ferroportin membrane expression, (iii) GPI (glycosylphosphatidylinositol)-linked Cp is the predominant form expressed in brain, (iv) Cp functions as a ferroxidase and regulates the oxidation of Fe2+ to Fe3+, (v) Cp does not bind to transferrin directly, and (vi) Cp is one member of a family of mammalian MCOs, which includes hephaestin. It is still unclear how an absence of Cp results in neurodegeneration: is the iron accumulation a primary or secondary injury? Although it is attractive to invoke an iron-mediated oxidative stress mechanism for the neuronal injury and degeneration in aceruloplasminaemia, our data suggest limited redox injury in the brains of mice lacking MCO. In fact, we propose a role for neuronal iron starvation with associated astrocyte and microglial iron overload. With the defect in aceruloplasminaemia being one of inefficient iron efflux from macrophages, we believe that the iron is trapped in a compartment not readily available to participate in oxyradical injury. It is likely that different mechanisms of neuronal cell protection are offered by astrocytes and microglia, and, once these cells are damaged, neuronal survival is compromised.

Original languageEnglish (US)
Pages (from-to)1277-1281
Number of pages5
JournalBiochemical Society transactions
Volume36
Issue number6
DOIs
StatePublished - Dec 1 2008

Keywords

  • Astrocyte
  • Ceruloplasmin
  • Hephaestin
  • Neurodegeneration
  • Neuron
  • Oxyradical

ASJC Scopus subject areas

  • Biochemistry

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