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Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments.

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 - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

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.

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Locomotion, motor coordination and nociception are impaired in Irp2−/− mice.Irp2−/− mice display reduced horizontal locomotor activity (total distance traveled, number of turns, number of total line crossings, mean velocity and angular velocity), and B) reduced vertical exploratory activity (number of rearing and rearing latency) assessed by the modified-Hole Board test [31]. C) Left panel, performance of Irp2−/− and WT mice on the accelerating rotarod in four trials on four consecutive trials with 15 min inter-trial-interval; right panel, decreased mean latency of Irp2−/− mice to fall off the rotarod (n = 4 trial; p = 0.055). D) 4-paw grip force test shows no difference in muscular strength between Irp2−/− and WT mice. E) Hot plate test shows increased hind paw licking in Irp2−/− mice. Data are given as the mean ± SEM; *p<0.05; **p<0.01, ***p<0.001, relative to WT; WT (n = 9) and Irp2−/− (n = 10).
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pone-0098072-g002: Locomotion, motor coordination and nociception are impaired in Irp2−/− mice.Irp2−/− mice display reduced horizontal locomotor activity (total distance traveled, number of turns, number of total line crossings, mean velocity and angular velocity), and B) reduced vertical exploratory activity (number of rearing and rearing latency) assessed by the modified-Hole Board test [31]. C) Left panel, performance of Irp2−/− and WT mice on the accelerating rotarod in four trials on four consecutive trials with 15 min inter-trial-interval; right panel, decreased mean latency of Irp2−/− mice to fall off the rotarod (n = 4 trial; p = 0.055). D) 4-paw grip force test shows no difference in muscular strength between Irp2−/− and WT mice. E) Hot plate test shows increased hind paw licking in Irp2−/− mice. Data are given as the mean ± SEM; *p<0.05; **p<0.01, ***p<0.001, relative to WT; WT (n = 9) and Irp2−/− (n = 10).

Mentions: As our Irp2−/− mice at 45–63 weeks old did not display tremors, kyphosis, or abnormal gait, we performed a battery of tests to assess behavioral and neurological function. We used the modified-Hole Board test to assay locomotor and exploratory activities, arousal, memory and social affinity, the modified SHIRPA test to assess neurological function, the grip strength test to quantify muscular strength and the accelerating rotarod to measure motor coordination and balance (Tables S4–S5). Irp2−/− mice displayed an overall reduction in forward locomotion, speed of movement and reduced vertical exploratory activities (rearing frequency and latency) (Figure 2A and B). Rotarod performance was slighty impaired in aged Irp2−/− mice compared to WT mice, which was not observed in 20-week old Irp2−/− mice, suggesting a progressive phenotype (Figure 2C and data not shown). The grip strength test (2-paws and 4-paws) revealed that muscular strength was not impaired in Irp2−/− mice (Figure 2D).


Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments.

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 - PLoS ONE (2014)

Locomotion, motor coordination and nociception are impaired in Irp2−/− mice.Irp2−/− mice display reduced horizontal locomotor activity (total distance traveled, number of turns, number of total line crossings, mean velocity and angular velocity), and B) reduced vertical exploratory activity (number of rearing and rearing latency) assessed by the modified-Hole Board test [31]. C) Left panel, performance of Irp2−/− and WT mice on the accelerating rotarod in four trials on four consecutive trials with 15 min inter-trial-interval; right panel, decreased mean latency of Irp2−/− mice to fall off the rotarod (n = 4 trial; p = 0.055). D) 4-paw grip force test shows no difference in muscular strength between Irp2−/− and WT mice. E) Hot plate test shows increased hind paw licking in Irp2−/− mice. Data are given as the mean ± SEM; *p<0.05; **p<0.01, ***p<0.001, relative to WT; WT (n = 9) and Irp2−/− (n = 10).
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pone-0098072-g002: Locomotion, motor coordination and nociception are impaired in Irp2−/− mice.Irp2−/− mice display reduced horizontal locomotor activity (total distance traveled, number of turns, number of total line crossings, mean velocity and angular velocity), and B) reduced vertical exploratory activity (number of rearing and rearing latency) assessed by the modified-Hole Board test [31]. C) Left panel, performance of Irp2−/− and WT mice on the accelerating rotarod in four trials on four consecutive trials with 15 min inter-trial-interval; right panel, decreased mean latency of Irp2−/− mice to fall off the rotarod (n = 4 trial; p = 0.055). D) 4-paw grip force test shows no difference in muscular strength between Irp2−/− and WT mice. E) Hot plate test shows increased hind paw licking in Irp2−/− mice. Data are given as the mean ± SEM; *p<0.05; **p<0.01, ***p<0.001, relative to WT; WT (n = 9) and Irp2−/− (n = 10).
Mentions: As our Irp2−/− mice at 45–63 weeks old did not display tremors, kyphosis, or abnormal gait, we performed a battery of tests to assess behavioral and neurological function. We used the modified-Hole Board test to assay locomotor and exploratory activities, arousal, memory and social affinity, the modified SHIRPA test to assess neurological function, the grip strength test to quantify muscular strength and the accelerating rotarod to measure motor coordination and balance (Tables S4–S5). Irp2−/− mice displayed an overall reduction in forward locomotion, speed of movement and reduced vertical exploratory activities (rearing frequency and latency) (Figure 2A and B). Rotarod performance was slighty impaired in aged Irp2−/− mice compared to WT mice, which was not observed in 20-week old Irp2−/− mice, suggesting a progressive phenotype (Figure 2C and data not shown). The grip strength test (2-paws and 4-paws) revealed that muscular strength was not impaired in Irp2−/− mice (Figure 2D).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

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.

Show MeSH
Related in: MedlinePlus