Cited by 160Neurological diseases and metabolismIron Metabolism and DisordersTrace Elements in Health

Aceruloplasminemia: An Inherited Neurodegenerative Disease with Impairment of Iron Homeostasis

XU, XUEYING, PIN, SOKHON, GATHINJI, MURAYA, FUCHS, RALPH, HARRIS, Z LEAH·2004·Annals of the New York Academy of Sciences

Abstract

A bstract : 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.

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Crossref · 10.1196/annals.1306.024

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Authors
XU, X., PIN, S., GATHINJI, M., FUCHS, R., & HARRIS, Z. L.
Affiliations
Johns Hopkins University (US)
Corresponding author
HARRIS, Z LEAH
Venue
Annals of the New York Academy of Sciences
Publisher
Wiley
Published
2004-03
Volume
1012
Issue
1
Pages
299-305
ISSN
  • 0077-8923 (ISSN-L)
  • 1749-6632
OpenAlex
W2002422090
Cited by
160
References
30
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 1 · 2021: 9 · 2020: 6 · 2019: 6 · 2018: 12 · 2017: 4 · 2016: 6 · 2015: 5 · 2014: 10 · 2013: 6 · 2012: 5
FWCI
0.92
Type
journal article
Language
en
Open access
closed
Locations
  • Annals of the New York Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5k08dk002464-04)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058086, DK02464, DK58086)
Topics
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
aceruloplasminemia, ceruloplasmin deficiency, iron homeostasis, iron overload, neurodegeneration, ferroxidase, multicopper oxidase, oxidative damage, copper homeostasis, diabetes mellitus, retinal degeneration, basal ganglia iron deposition, autosomal recessive disorder
MeSH terms
Animals, Apoproteins, Brain, Ceruloplasmin, Copper, Heart, Homeostasis, Humans, Iron, Liver, Pancreas, Neurodegenerative Diseases

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