Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene

Ana G. Barbeito, Holly Garringer, Martin A. Baraibar, Xiaoying Gao, Miguel Arredondo, Marco T. Núñez, Mark A. Smith, Bernardino Ghetti, Ruben Vidal

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Insertional mutations in exon 4 of the ferritin light chain (FTL) gene are associated with hereditary ferritinopathy (HF) or neuroferritinopathy, an autosomal dominant neurodegenerative disease characterized by progressive impairment of motor and cognitive functions. To determine the pathogenic mechanisms by which mutations in FTL lead to neurodegeneration, we investigated iron metabolism and markers of oxidative stress in the brain of transgenic (Tg) mice that express the mutant human FTL498-499InsTC cDNA. Compared with wild-type mice, brain extracts from Tg (FTL-Tg) mice showed an increase in the cytoplasmic levels of both FTL and ferritin heavy chain polypeptides, a decrease in the protein and mRNA levels of transferrin receptor-1, and a significant increase in iron levels. Transgenic mice also showed the presence of markers for lipid peroxidation, protein carbonyls, and nitrone-protein adducts in the brain. However, gene expression analysis of iron management proteins in the liver of Tg mice indicates that the FTL-Tg mouse liver is iron deficient. Our data suggest that disruption of iron metabolism in the brain has a primary role in the process of neurodegeneration in HF and that the pathogenesis of HF is likely to result from a combination of reduction in iron storage function and enhanced toxicity associated with iron-induced ferritin aggregates in the brain.

Original languageEnglish
Pages (from-to)1067-1078
Number of pages12
JournalJournal of Neurochemistry
Volume109
Issue number4
DOIs
StatePublished - May 2009

Fingerprint

Oxidative stress
Apoferritins
Ferritins
Metabolism
Oxidative Stress
Iron
Genes
Transgenic Mice
Light
Peptides
Brain
Liver
Proteins
Neurodegenerative diseases
Mutation
Transferrin Receptors
Gene expression
Neurodegenerative Diseases
Cognition
Lipid Peroxidation

Keywords

  • Animal model
  • Hereditary ferritinopathy
  • Neuroferritinopathy

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. / Barbeito, Ana G.; Garringer, Holly; Baraibar, Martin A.; Gao, Xiaoying; Arredondo, Miguel; Núñez, Marco T.; Smith, Mark A.; Ghetti, Bernardino; Vidal, Ruben.

In: Journal of Neurochemistry, Vol. 109, No. 4, 05.2009, p. 1067-1078.

Research output: Contribution to journalArticle

Barbeito, Ana G. ; Garringer, Holly ; Baraibar, Martin A. ; Gao, Xiaoying ; Arredondo, Miguel ; Núñez, Marco T. ; Smith, Mark A. ; Ghetti, Bernardino ; Vidal, Ruben. / Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. In: Journal of Neurochemistry. 2009 ; Vol. 109, No. 4. pp. 1067-1078.
@article{d4f221847abc4d509ece147dae4e2733,
title = "Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene",
abstract = "Insertional mutations in exon 4 of the ferritin light chain (FTL) gene are associated with hereditary ferritinopathy (HF) or neuroferritinopathy, an autosomal dominant neurodegenerative disease characterized by progressive impairment of motor and cognitive functions. To determine the pathogenic mechanisms by which mutations in FTL lead to neurodegeneration, we investigated iron metabolism and markers of oxidative stress in the brain of transgenic (Tg) mice that express the mutant human FTL498-499InsTC cDNA. Compared with wild-type mice, brain extracts from Tg (FTL-Tg) mice showed an increase in the cytoplasmic levels of both FTL and ferritin heavy chain polypeptides, a decrease in the protein and mRNA levels of transferrin receptor-1, and a significant increase in iron levels. Transgenic mice also showed the presence of markers for lipid peroxidation, protein carbonyls, and nitrone-protein adducts in the brain. However, gene expression analysis of iron management proteins in the liver of Tg mice indicates that the FTL-Tg mouse liver is iron deficient. Our data suggest that disruption of iron metabolism in the brain has a primary role in the process of neurodegeneration in HF and that the pathogenesis of HF is likely to result from a combination of reduction in iron storage function and enhanced toxicity associated with iron-induced ferritin aggregates in the brain.",
keywords = "Animal model, Hereditary ferritinopathy, Neuroferritinopathy",
author = "Barbeito, {Ana G.} and Holly Garringer and Baraibar, {Martin A.} and Xiaoying Gao and Miguel Arredondo and N{\'u}{\~n}ez, {Marco T.} and Smith, {Mark A.} and Bernardino Ghetti and Ruben Vidal",
year = "2009",
month = "5",
doi = "10.1111/j.1471-4159.2009.06028.x",
language = "English",
volume = "109",
pages = "1067--1078",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene

AU - Barbeito, Ana G.

AU - Garringer, Holly

AU - Baraibar, Martin A.

AU - Gao, Xiaoying

AU - Arredondo, Miguel

AU - Núñez, Marco T.

AU - Smith, Mark A.

AU - Ghetti, Bernardino

AU - Vidal, Ruben

PY - 2009/5

Y1 - 2009/5

N2 - Insertional mutations in exon 4 of the ferritin light chain (FTL) gene are associated with hereditary ferritinopathy (HF) or neuroferritinopathy, an autosomal dominant neurodegenerative disease characterized by progressive impairment of motor and cognitive functions. To determine the pathogenic mechanisms by which mutations in FTL lead to neurodegeneration, we investigated iron metabolism and markers of oxidative stress in the brain of transgenic (Tg) mice that express the mutant human FTL498-499InsTC cDNA. Compared with wild-type mice, brain extracts from Tg (FTL-Tg) mice showed an increase in the cytoplasmic levels of both FTL and ferritin heavy chain polypeptides, a decrease in the protein and mRNA levels of transferrin receptor-1, and a significant increase in iron levels. Transgenic mice also showed the presence of markers for lipid peroxidation, protein carbonyls, and nitrone-protein adducts in the brain. However, gene expression analysis of iron management proteins in the liver of Tg mice indicates that the FTL-Tg mouse liver is iron deficient. Our data suggest that disruption of iron metabolism in the brain has a primary role in the process of neurodegeneration in HF and that the pathogenesis of HF is likely to result from a combination of reduction in iron storage function and enhanced toxicity associated with iron-induced ferritin aggregates in the brain.

AB - Insertional mutations in exon 4 of the ferritin light chain (FTL) gene are associated with hereditary ferritinopathy (HF) or neuroferritinopathy, an autosomal dominant neurodegenerative disease characterized by progressive impairment of motor and cognitive functions. To determine the pathogenic mechanisms by which mutations in FTL lead to neurodegeneration, we investigated iron metabolism and markers of oxidative stress in the brain of transgenic (Tg) mice that express the mutant human FTL498-499InsTC cDNA. Compared with wild-type mice, brain extracts from Tg (FTL-Tg) mice showed an increase in the cytoplasmic levels of both FTL and ferritin heavy chain polypeptides, a decrease in the protein and mRNA levels of transferrin receptor-1, and a significant increase in iron levels. Transgenic mice also showed the presence of markers for lipid peroxidation, protein carbonyls, and nitrone-protein adducts in the brain. However, gene expression analysis of iron management proteins in the liver of Tg mice indicates that the FTL-Tg mouse liver is iron deficient. Our data suggest that disruption of iron metabolism in the brain has a primary role in the process of neurodegeneration in HF and that the pathogenesis of HF is likely to result from a combination of reduction in iron storage function and enhanced toxicity associated with iron-induced ferritin aggregates in the brain.

KW - Animal model

KW - Hereditary ferritinopathy

KW - Neuroferritinopathy

UR - http://www.scopus.com/inward/record.url?scp=65649154118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65649154118&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2009.06028.x

DO - 10.1111/j.1471-4159.2009.06028.x

M3 - Article

C2 - 19519778

AN - SCOPUS:65649154118

VL - 109

SP - 1067

EP - 1078

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 4

ER -