Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland, USA
Address for correspondence: Z. Leah Harris, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital and School of Medicine, 600 North Wolfe Street, Blalock 904B, Baltimore, MD 21287. Voice 410-502-4199; fax: 410-502-5312. zharris1{at}jhmi.edu
Ann N.Y. Acad. Sci. 1012: 299-305 (2004).
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.
