Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice
Supplemental File 5
AuthorsJeong, Suh Young
Crooks, Daniel R.
Ghosh, Manik C.
Mitchell, James B.
Rouault, Tracey A.
MetadataShow full item record
AbstractGenetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.
CitationJeong SY, Crooks DR, Wilson-Ollivierre H, Ghosh MC, Sougrat R, et al. (2011) Iron Insufficiency Compromises Motor Neurons and Their Mitochondrial Function in Irp2-Null Mice. PLoS ONE 6: e25404. doi:10.1371/journal.pone.0025404.
PublisherPublic Library of Science (PLoS)
PubMed Central IDPMC3189198
- Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice.
- Authors: Ghosh MC, Tong WH, Zhang D, Ollivierre-Wilson H, Singh A, Krishna MC, Mitchell JB, Rouault TA
- Issue date: 2008 Aug 19
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- Issue date: 2006 Mar-Apr
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- Issue date: 2011 Jul 1
- Severity of neurodegeneration correlates with compromise of iron metabolism in mice with iron regulatory protein deficiencies.
- Authors: Smith SR, Cooperman S, Lavaute T, Tresser N, Ghosh M, Meyron-Holtz E, Land W, Ollivierre H, Jortner B, Switzer R 3rd, Messing A, Rouault TA
- Issue date: 2004 Mar
- Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments.
- Authors: Zumbrennen-Bullough KB, Becker L, Garrett L, Hölter SM, Calzada-Wack J, Mossbrugger I, Quintanilla-Fend L, Racz I, Rathkolb B, Klopstock T, Wurst W, Zimmer A, Wolf E, Fuchs H, Gailus-Durner V, de Angelis MH, Romney SJ, Leibold EA
- Issue date: 2014
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