Redox active iron accumulation in aceruloplasminemia

Luis F. Gonzalez-Cuyar, George Perry, Hiroaki Miyajima, Craig S. Atwood, Marcela Riveros-Angel, Patrick F. Lyons, Sandra L. Siedlak, Mark A. Smith, Rudy J. Castellani

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Aceruloplasminemia is an autosomal recessive disorder characterized by a ceruloplasmin gene mutation and defective or absent ceruloplasmin function. Because ceruloplasmin functions in iron transport and storage, aceruloplasminemia leads to excessive iron accumulation systemically and within the CNS. The type and form of iron deposited is unclear and while oxidative stress was hypothesized as a potential mechanism of cytotoxicity in this disorder, direct evidence linking oxidative stress to the underlying genetic defect has not been provided. To address these issues, we studied autopsy brain tissue from two subjects with genetically confirmed aceruloplasminemia using an assay developed in our laboratory for redox-active iron assessment. We found iron deposited in perivascular areas, localizing to terminal astrocytic processes and further showed that this iron was redox active. These data are consistent with the concept that oxidative stress, driven by heavy metal accumulation, represents the primary cellular cytotoxic process, accounting for neuronal damage in affected brain regions. As such, aceruloplasminemia is an excellent model of transition metal-driven oxidative stress and neurodegeneration.

Original languageEnglish (US)
Pages (from-to)466-471
Number of pages6
JournalNeuropathology
Volume28
Issue number5
DOIs
StatePublished - Oct 2008
Externally publishedYes

Keywords

  • Aceruloplasminemia
  • Ceruloplasmin
  • Iron
  • Oxidative stress

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology

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