title: Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice.
abstract: In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.
authors.affiliation: Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
authors.forename: T
authors.initials: T
authors.lastname: LaVaute
authors.forename: S
authors.initials: S
authors.lastname: Smith
authors.forename: S
authors.initials: S
authors.lastname: Cooperman
authors.forename: K
authors.initials: K
authors.lastname: Iwai
authors.forename: W
authors.initials: W
authors.lastname: Land
authors.forename: E
authors.initials: E
authors.lastname: Meyron-Holtz
authors.forename: S K
authors.initials: SK
authors.lastname: Drake
authors.forename: G
authors.initials: G
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Abu-Asab
authors.forename: M
authors.initials: M
authors.lastname: Tsokos
authors.forename: R
authors.initials: R
authors.lastname: Switzer
authors.forename: A
authors.initials: A
authors.lastname: Grinberg
authors.forename: P
authors.initials: P
authors.lastname: Love
authors.forename: N
authors.initials: N
authors.lastname: Tresser
authors.forename: T A
authors.initials: TA
authors.lastname: Rouault
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology; D004386:Duodenum / Q000473:pathology; D005293:Ferritins / Q000378:metabolism; D017353:Gene Deletion; D007413:Intestinal Mucosa / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology; D011699:Putamen / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics*; D020218:Response Elements; D013788:Thalamus / Q000473:pathology; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D016601:RNA-Binding Proteins; D014452:Ubiquitins; D005293:Ferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2