Aceruloplasminemia: An inherited neurodegenerative disease with impairment of iron homeostasis

Xueying Xu, Sokhon Pin, Muraya Gathinji, Ralph Fuchs, Z. Leah Harris*

*Corresponding author for this work

Research output: Contribution to journalReview article

115 Scopus citations

Abstract

In 1987, Miyajima et al. first characterized an autosomal recessive, adult-onset neurodegenerative disorder resembling Parkinson's disease associated with near-absent circulating serum ceruloplasmin levels. Coined "familial apoceruloplasmin deficiency", they described a patient with a presenting triad of diabetes mellitus, retinal degeneration, and neurodegeneration with blepharospasm. Neuropathological evaluation revealed abundant iron deposition in selected neurons of the basal ganglia and substantia nigra with associated neuronal dropout and spongioform degeneration without evidence of reactive gliosis. Subsequently, mutations in the ceruloplasmin gene have been determined to result in the excessive iron accumulation seen in the pancreas, retina, and brain. Elevated serum ferritin suggests a systemic iron overload syndrome, yet affected patients had low transferrin saturation and a mild anemia. This new disease, " aceruloplasminemia", reveals a role for ceruloplasmin as an essential ferroxidase critical for iron homeostasis. This multicopper oxidase promotes efficient iron efflux such that individuals lacking ceruloplasmin develop a presumed oxidative injury secondary to iron accumulation and significant neuronal damage. Aceruloplasminemic mice provide a valuable model to further study the mechanisms by which ceruloplasmin regulates iron trafficking and the role of iron in oxidative injury. Despite the dependence of ceruloplasmin on copper for its function, aceruloplasminemia represents an iron storage disease and not a defect in copper metabolism. However, recent evidence in Saccharomyces cerevisiae indicates that Fet3, the yeast homologue of ceruloplasmin, functions as an essential cuprous oxidase. Further investigation into the mechanisms by which ceruloplasmin regulates iron and copper homeostasis will provide valuable insight into the pathogenesis of metallo-mediated diseases and elucidate mechanisms for transition metal (copper, iron) neuropathology.

Original languageEnglish (US)
Pages (from-to)299-305
Number of pages7
JournalAnnals of the New York Academy of Sciences
Volume1012
DOIs
StatePublished - 2004

Keywords

  • Aceruloplasminemia
  • Ceruloplasmin
  • Fet3
  • Homeostasis
  • Iron

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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