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PLoS One. 2014 Jun 4;9(6):e98072. doi: 10.1371/journal.pone.0098072. eCollection 2014.

Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments.

Author information

1
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.
2
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.
3
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.
4
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.
5
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.
6
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.
7
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.
8
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.
9
Institute of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
10
Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universitat, Munich, Germany.
11
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.
12
University of Utah, Department of Medicine, Division of Hematology and Hematological Malignancies, Salt Lake City, Utah, United States of America.

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.

PMID:
24896637
PMCID:
PMC4045679
DOI:
10.1371/journal.pone.0098072
[Indexed for MEDLINE]
Free PMC Article

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