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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Ana G
authors.initials: AG
authors.lastname: Barbeito
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Garringer
authors.forename: Martin A
authors.initials: MA
authors.lastname: Baraibar
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Gao
authors.forename: Miguel
authors.initials: M
authors.lastname: Arredondo
authors.forename: Marco T
authors.initials: MT
authors.lastname: Núñez
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Ruben
authors.initials: R
authors.lastname: Vidal
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000235:genetics* / Q000502:physiology*; D001923:Brain Chemistry / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons / Q000235:genetics; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D019189:Iron Metabolism Disorders / Q000235:genetics* / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019159:Nonheme Iron Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*
chemical_list: C507433:FTL protein, human; D019159:Nonheme Iron Proteins; D001052:Apoferritins; D007501:Iron