title: Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy.
abstract: Mutations in the ferritin light chain (FTL) gene cause the neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic iron-containing ferritin inclusion bodies (IBs) in glia and neurons throughout the central nervous system (CNS) and in tissues of multiple organ systems. Herein, using primary mouse embryonic fibroblasts from a mouse model of HF, we show significant intracellular accumulation of ferritin and an increase in susceptibility to oxidative damage when cells are exposed to iron. Treatment of the cells with the iron chelator deferiprone (DFP) led to a significant improvement in cell viability and a decrease in iron content. In vivo, iron overload and DFP treatment of the mouse model had remarkable effects on systemic iron homeostasis and ferritin deposition, without significantly affecting CNS pathology. Our study highlights the role of iron in modulating ferritin aggregation in vivo in the disease HF. It also puts emphasis on the potential usefulness of a therapy based on chelators that can target the CNS to remove and redistribute iron and to resolubilize or prevent ferritin aggregation while maintaining normal systemic iron stores.
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Holly J
authors: HJ
authors: Garringer
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Jose M
authors: JM
authors: Irimia
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Wei
authors: W
authors: Li
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Charles B
authors: CB
authors: Goodwin
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Briana
authors: B
authors: Richine
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Anthony
authors: A
authors: Acton
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Rebecca J
authors: RJ
authors: Chan
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Munro
authors: M
authors: Peacock
authors: Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indianam 46202, United States of America.
authors: Barry B
authors: BB
authors: Muhoberac
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Bernardino
authors: B
authors: Ghetti
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 46202, United States of America.
authors: Ruben
authors: R
authors: Vidal
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D015913:Chelation Therapy; D000077543:Deferiprone; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000009:adverse effects; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000494:pharmacology; D019189:Iron Metabolism Disorders / Q000188:drug therapy* / Q000378:metabolism; D019190:Iron Overload / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D019150:Neuroaxonal Dystrophies / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C507433:FTL protein, human; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D001052:Apoferritins; D007501:Iron