title: Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone.
abstract: Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. Above: Iron (Fe) normally moves from capillaries to glia to neurons. It is exported from the glia by ferroportin (Fpn) with ferroxidases ceruloplasmin (Cp) and/or Hephaestin (Heph). Below: In mice with mutation of Cp and Heph, iron accumulates in glia, while neurons have low iron levels. Both neurons and glia degenerate and mice become ataxic unless given an iron chelator.
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Ophthalmology, The Second Hospital of Jilin University, Jilin, China.
authors: Liangliang
authors: L
authors: Zhao
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors: Majda
authors: M
authors: Hadziahmetovic
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Ophthalmology, The Second Hospital of Jilin University, Jilin, China.
authors: Chenguang
authors: C
authors: Wang
authors: Department of Medicine, Sinai Hospital, Baltimore, Maryland, USA.
authors: Xueying
authors: X
authors: Xu
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Ying
authors: Y
authors: Song
authors: Departments of Neurology, Human Genetics and Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors: H A
authors: HA
authors: Jinnah
authors: ApoPharma Inc, Toronto, California, USA.
authors: Jolanta
authors: J
authors: Wodzinska
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Jared
authors: J
authors: Iacovelli
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Natalie
authors: N
authors: Wolkow
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Predrag
authors: P
authors: Krajacic
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Alyssa Cwanger
authors: AC
authors: Weissberger
authors: ApoPharma Inc, Toronto, California, USA.
authors: John
authors: J
authors: Connelly
authors: ApoPharma Inc, Toronto, California, USA.|Leslie Dan Faculty of Pharmacy, University of Toronto M5S 3M2, Toronto, Canada.
authors: Michael
authors: M
authors: Spino
authors: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Michael K
authors: MK
authors: Lee
authors: Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.
authors: James
authors: J
authors: Connor
authors: Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors: Benoit
authors: B
authors: Giasson
authors: Department of Pediatrics, Northwestern University, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
authors: Z Leah
authors: ZL
authors: Harris
authors: F.M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Joshua L
authors: JL
authors: Dunaief
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002570:Ceruloplasmin / Q000235:genetics* / Q000378:metabolism; D000077543:Deferiprone; D004195:Disease Models, Animal; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D053580:Muscle Strength / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011728:Pyridones / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C117324:Heph protein, mouse; D007502:Iron Chelating Agents; C499047:Mbp protein, mouse; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D011728:Pyridones; D000077543:Deferiprone; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D002570:Ceruloplasmin
keywords: ceruloplasmin/Hephaestin; deferiprone; glia; iron; neurodegeneration; oxidative stress