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

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; Rouault, Tracey A.

doi:10.1038/84859

Cited by 509Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

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

LaVaute, Timothy, Smith, Sophia, Cooperman, Sharon, Iwai, Kazuhiro, Land, William, Meyron-Holtz, Esther, Drake, Steven K., Miller, Georgina +7 more·2001·Nature Genetics

DOI 10.1038/84859

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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 metabo…

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“The H subunit has ferroxidase activity, which converts Fe2+ to Fe3+ for storage inside the shell (178)”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [178]
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“The same group demonstrated the ferroxidase activity of yeast frataxin (233) [similar to that of ferritin H, which oxidizes Fe2+ to Fe3+ (178)].”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [178]

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Authors: LaVaute, T., Smith, S., Cooperman, S., Iwai, K., Land, W., Meyron-Holtz, E., Drake, S. K., Miller, G., Abu-Asab, M., Tsokos, M., Switzer, R., Grinberg, A., Love, P., Tresser, N., & Rouault, T. A.
Affiliations: National Institutes of Health (US)
National Cancer Institute (US)
Corresponding author: Rouault, Tracey A.
ORCID: Drake, Steven K.
Abu-Asab, Mones
Tsokos, Maria
Love, Paul
Rouault, Tracey A.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2001-02
Volume: 27
Issue: 2
Pages: 209-214
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/84859
OpenAlex: W1530657831
Cited by: 509
References: 30
Citations by year: 2026: 7 · 2025: 11 · 2024: 29 · 2023: 19 · 2022: 12 · 2021: 15 · 2020: 16 · 2019: 21 · 2018: 15 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 19 · 2013: 16 · 2012: 23
FWCI: 16.91
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords: IRP2, iron metabolism, iron-responsive element, neurodegeneration, movement disorders, ataxia, brain iron accumulation, ferritin, oligodendrocytes, ubiquitin-positive inclusions, transferrin receptor, knockout mice, central nervous system
MeSH terms: Animals, Cerebellum, Duodenum, Ferritins, Intestinal Mucosa, Iron, Iron-Sulfur Proteins, Mice, Mutant Strains, Molecular Sequence Data, Movement Disorders, Neurons, Oligodendroglia, Purkinje Cells, Putamen, Thalamus, Ubiquitins, RNA-Binding Proteins, Gene Deletion, Neurodegenerative Diseases, Response Elements, Iron-Regulatory Proteins, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Mice

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

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