Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain

Magaki, Shino; Mueller, Claudius; Yellon, Steven M.; Fox, James M.; Kim, Joseph; Snissarenko, Eugene P.; Chin, V.; Ghosh, Manik C.; Kirsch, Wolff M.

doi:10.1016/j.brainres.2007.05.004

Cited by 9 publications

(11 citation statements)

References 36 publications

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“…Magaki et al . 55 measured “loosely bound iron” and “non-heme iron”, defined operationally, in 6, 12, and 24 week old mouse brains. They found that loosely bound Fe represented 20% – 30% of non-heme Fe, with the latter type of Fe increasing with age and the former decreasing slightly or remaining constant.…”

Section: Discussionmentioning

confidence: 99%

Changing iron content of the mouse brain during development

et al. 2012

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Iron is crucial to many processes in the brain yet the percentages of the major iron-containing species contained therein, and how these percentages change during development, have not been reliably determined. To do this, C57BL/6 mice were enriched in 57Fe and their brains were examined by Mössbauer, EPR, and electronic absorption spectroscopy; Fe concentrations were evaluated using ICP-MS. Excluding the contribution of residual blood hemoglobin, the three major categories of brain Fe included ferritin (an iron storage protein), mitochondrial iron (consisting primarily of Fe/S clusters and hemes), and mononuclear nonheme high-spin (NHHS) FeII and FeIII species. Brains from prenatal and one-week old mice were dominated by ferritin and were deficient in mitochondrial Fe. During the next few weeks of life, the brain grew and experienced a burst of mitochondriogenesis. Overall brain Fe concentration and the concentration of ferritin declined during this burst phase, suggesting that the rate of Fe incorporation was insufficient to accommodate these changes. The slow rate of Fe import and export to/from the brain, relative to other organs, was verified by an isotopic labeling study. Iron levels and ferritin stores replenished in young adult mice. NHHS FeII species were observed in substantial levels in brains of several ages. A stable free-radical species that increased with age was observed by EPR spectroscopy. Brains from mice raised on an Fe-deficient diet showed depleted ferritin iron but normal mitochondrial iron levels.

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Section: Discussionmentioning

confidence: 99%

Changing iron content of the mouse brain during development

et al. 2012

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“…More than three-fold increases of ferritin were directly observed in the 3D distribution of ferritin by electron tomography in different regions of brains of Irp1 +/− Irp2 −/− mice, and structural damage was observed within the axons (Zhang et al, 2005). The Kirsch group found that both loosely bound iron and non-heme iron increased during development between 6 and 12 weeks of age in Irp2 −/− mice, whereas the reverse was observed for WT mice (Magaki et al, 2007). …”

Section: The First Irp2 Knockout Mouse Modelmentioning

confidence: 99%

Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins

Ghosh¹,

Zhang²,

Rouault³

2015

Neurobiology of Disease

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Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive elements (IREs) that are found in the untranslated regions of target mRNAs that encode proteins involved in iron metabolism. IRPs modify expression of iron metabolism genes, and global and tissue-specific knockout mice have been made to evaluate the physiological significance of these iron regulatory proteins (Irps). Here, we will discuss the results of the studies that have been performed with mice engineered to lack expression of one or both Irps, and made in different strains using different methodologies. Both Irp1 and Irp2 knockout mice are viable, but the double knockout (Irp1−/−Irp2−/−) mice die before birth, indicating that these Irps play a crucial role in maintaining iron homeostasis. Irp1−/− mice develop polycythemia and pulmonary hypertension, and when these mice are challenged with a low iron diet, they die early of abdominal hemorrhages, suggesting that Irp1 plays an essential role in erythropoiesis and in the pulmonary and cardiovascular systems. Irp2−/− mice develop microcytic anemia, erythropoietic protoporphyria and a progressive neurological disorder, indicating that Irp2 has important functions in the nervous system and erythropoietic homeostasis. Several excellent review articles have recently been published on Irp knockout mice that mainly focus on Irp1−/− mice (referenced in the introduction). In this review, we will briefly describe the phenotypes and physiological implications of Irp1−/− mice, and will discuss the phenotypes observed for Irp2−/− mice in detail with a particular emphasis on the neurological problems of these mice.

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“…Aberrant brain metal levels have been associated with normal aging and a variety of diseases however this is still debated [19, 258]. …”

Section: Putative Causes and Risk Factors Involved In Pdmentioning

confidence: 99%

Targeting the Progression of Parkinsons Disease

George¹,

Mok

Moses

et al. 2009

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By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease.

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Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain

Cited by 9 publications

References 36 publications

Changing iron content of the mouse brain during development

Changing iron content of the mouse brain during development

Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins

Targeting the Progression of Parkinsons Disease

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