Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice

• Published in: Nature genetics Vol. 27; no. 2; pp. 209 - 214
• Main Authors: Rouault, Tracey A, LaVaute, Timothy, Smith, Sophia, Cooperman, Sharon, Iwai, Kazuhiro, Land, William, Meyron-Holtz, Esther, Drake, Steven K, Miller, Georgina, Abu-Asab, Mones, Tsokos, Maria, Switzer, Robert, Grinberg, Alexander, Love, Paul, Tresser, Nancy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-02-2001
• Subjects: Animals; Ataxia; Biological and medical sciences; bradykinesia; Central nervous system; Cerebellum - pathology; Childrens health; Complications and side effects; Degeneration; Diagnosis; Disease; Duodenum - pathology; Ferritins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene mutations; Genes. Genome; Genetic aspects; Identification and classification; Intestinal Mucosa - pathology; Ireb2 gene; Iron; Iron - metabolism; Iron metabolism disorders; Iron Regulatory Protein 1; Iron Regulatory Protein 2; iron responsive elements; Iron-Regulatory Proteins; Iron-Sulfur Proteins - genetics; Mammals; Metabolism; Mice; Mice, Mutant Strains; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Movement disorders; Movement Disorders - genetics; Nervous system; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurons - pathology; Oligodendroglia - pathology; Proteins; Publishing; Purkinje Cells - pathology; Putamen - pathology; Response Elements; Risk factors; RNA-Binding Proteins - genetics; Thalamus - pathology; Ubiquitins - metabolism; United States; United States > US; Maryland; Vertebrata; Regulation(control); Mammalia; Targeting; Gene; Mouse; Rodentia; Iron; Mutation; Gene expression; Metabolism; Protein
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/84859

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.