Abstract
Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2−/− mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2−/− mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments.
Highlights
Iron is essential for growth and proliferation of mammalian cells due to its role as a protein cofactor for hemoglobin synthesis, DNA synthesis and mitochondrial respiration
Irp22/2 mice showed mild microcytic anemia characterized by reduced hemoglobin, hematocrit and mean corpuscular volume (Table S1)
Our data show that mice with a global Irp2 deficiency recapitulate the main features of other Irp2 deficient mouse models such as microcytic anemia, erythropoietic protoporphyria, altered body iron distribution and altered expression of ferritin and TfR1 in tissues
Summary
Iron is essential for growth and proliferation of mammalian cells due to its role as a protein cofactor for hemoglobin synthesis, DNA synthesis and mitochondrial respiration. Dysregulation of iron homeostasis caused by iron excess or iron deficiency leads to hematological, metabolic and neurodegenerative diseases [1,2,3]. Two NBIA diseases, hereditary ferritinopathy and aceruloplasminemia, caused by mutations in the ferritin-L subunit gene (FTL) [9] and in the ceruloplasmin (CP) gene [10], respectively, suggest that abnormal iron metabolism is the pathologic event leading to neurodegeneration in these disorders. These studies highlight the importance of maintaining brain iron within a physiological range to avoid the adverse consequences of iron depletion or excess
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