title: Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments.
abstract: Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2-/- mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2-/- mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments.
authors.affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Zumbrennen-Bullough
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Development Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Lillian
authors.initials: L
authors.lastname: Garrett
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Development Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Pathology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Pathology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Mossbrugger
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Pathology, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Fend
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Racz
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universitat, Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Klinikum der Ludwig-Maximilians-Universitat, Munich, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Institute of Development Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Chair of Developmental Genetics, Technische Universitat München, Freising-Weihenstephan, Germany; Max Planck Institute of Psychiatry, Munich, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universitat, Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universitat München, Freising, Germany; German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: University of Utah, Department of Medicine, Division of Hematology and Hematological Malignancies, Salt Lake City, Utah, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Romney
authors.affiliation: University of Utah, Department of Medicine, Division of Hematology and Hematological Malignancies, Salt Lake City, Utah, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Leibold
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005106:Exploratory Behavior / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D059225:Nociception / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D066127:White Matter / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D007501:Iron; D035942:Iron Regulatory Protein 2