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

Nature Genetics volume 27, pages 209–214 (2001)Cite this article

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 cells1,2. 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.

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Figure 1: Generation and phenotype of Ireb2−/− mice.
Figure 2: Ferric iron accumulates in the duodenal mucosa of Ireb2−/− mice, and expression levels of ferritin, both splice forms of Dmt1 and the basolateral iron exporter are high relative to controls on a normal diet.
Figure 3: Iron accumulates in white matter tracts of the caudate-putamen and thalamus in Ireb2−/− mice and increases with age.
Figure 4: Iron accumulation and axonal degeneration colocalize in the cerebellar white matter of Ireb2−/− mice and cerebellar oligodendrocytes of Ireb2−/− mice accumulate cytosolic iron and form ubiquitin inclusions.
Figure 5: Neuronal iron accumulation is associated with ultrastructural evidence of neurodegeneration in Ireb2−/− mice.
Figure 6: Purkinje cells degenerate in Ireb2−/− mice and increased Purkinje axonal ferritin expression colocalizes with increased iron accumulation in Ireb2−/− mice.

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Acknowledgements

We thank J. Gitlin for performing serum ceruloplasmin measurements; E.Mezey for help with detection of ubiquitin inclusions; A.M. Konijn for mouse liver ferritin and rabbit anti-mouse ferritin antiserum coupled to β-galactosidase; R. Levine for the overexpressed Irp2 degradation domain; and S. Landis and members of the Rouault group and Cell Biology and Metabolism Branch for suggestions. This work was supported by the Intramural program of the National Institute of Child Health and Human Development, and in part by the Lookout Fund.

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Authors and Affiliations

  1. Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Maryland, USA

    Timothy LaVaute, Sophia Smith, Sharon Cooperman, Kazuhiro Iwai, William Land, Esther Meyron-Holtz, Steven K. Drake & Tracey A. Rouault

  2. Veterinary Resources Program, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA

    Georgina Miller

  3. Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland, USA

    Mones Abu-Asab & Maria Tsokos

  4. NeuroScience Associates, Knoxville, Tennessee, USA

    Robert Switzer III

  5. Laboratory of Mammalian Genetics and Development, National Institute of Child Health and Human Development, Bethesda, Maryland, USA

    Alexander Grinberg & Paul Love

  6. Neuroimmunology Branch, National Institute of Neurologic Disease and Stroke, Bethesda, Maryland, USA

    Nancy Tresser

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  1. Timothy LaVaute
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Correspondence to Tracey A. Rouault.

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LaVaute, T., Smith, S., Cooperman, S. et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet 27, 209–214 (2001). https://doi.org/10.1038/84859

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