P4‐187: Iron regulatory protein 2 is involved in brain copper homeostasis

Mueller, Claudius; Magaki, Shino; Schrag, Matthew; Ghosh, Manik C.; Kirsch, Wolff M.

doi:10.1016/j.jalz.2009.04.754

Cited by 4 publications

(4 citation statements)

References 32 publications

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“…In particular, some studies have shown that IRPs are implicated in Fe regulation in the brain. For instance, APP levels are modulated by IRP1 [57] and its expression is upregulated in the hippocampus of IREB2−/− mice [60]. Moreover, it was also shown that downregulation of ACO1 expression is induced by hypoxia [61].…”

Section: Discussionmentioning

confidence: 97%

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Guerreiro

Silva

Crespo

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Alzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.

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Section: Discussionmentioning

confidence: 97%

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Guerreiro

Silva

Crespo

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Smith and colleagues showed abnormal localization of IRP2 in the brain tissue of Alzheimer patients more than a decade ago (Smith et al, 1998). Kirsch and his collaborators reported decreased levels of copper and increased expression of amyloid β precursor protein (AβPP) in the hippocampus of Irp2 −/− mice suggesting that IRP2 may have a significant role in Alzheimer’s disease (Mueller et al, 2009). Recently, Rogers and his colleagues found that the amyloid precursor protein (APP) also has an IRE-like RNA stem loop in its 5′ untranslated region, and that IRP1 selectively binds to this APP IRE in human neural cells (Bandyopadhyay et al, 2013, 2014; Cho et al, 2010).…”

Section: Iron Regulatory Proteins and Alzheimer Diseasementioning

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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“…These findings have been recently confirmed in a novel IRP2 knockout mouse line characterized by locomotor dysfunction and iron accumulation in the brain regions coordinating muscle function (Zumbrennen K. et al, 2009, Abstract, page 69, International BioIron Society Meeting, Porto, Portugal). It has also been reported that IRP2 deletion affects brain copper levels in young mice (139), which may have significant implications for neurodegenerative diseases characterized by altered copper levels, such as Alzheimer's disease. Interestingly, IRP2-deficient mice do not seem to accumulate iron in the pancreas, but have hyperglycemia and impaired pancreatic beta cell function (Zumbrennen K. et al, 2009, Abstract, page 81 International BioIron Society Meeting, Porto, Portugal).…”

Section: A Effects Of Irp1 and Irp2 Deficiencymentioning

confidence: 99%

Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

Recalcati

Minotti²,

Cairo

2010

Antioxidants & Redox Signaling

106

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Eukaryotic cells require iron for survival but, as an excess of poorly liganded iron can lead to the catalytic production of toxic radicals that can damage cell structures, regulatory mechanisms have been developed to maintain appropriate cell and body iron levels. The interactions of iron responsive elements (IREs) with iron regulatory proteins (IRPs) coordinately regulate the expression of the genes involved in iron uptake, use, storage, and export at the post-transcriptional level, and represent the main regulatory network controlling cell iron homeostasis. IRP1 and IRP2 are similar (but not identical) proteins with partially overlapping and complementary functions, and control cell iron metabolism by binding to IREs (i.e., conserved RNA stem-loops located in the untranslated regions of a dozen mRNAs directly or indirectly related to iron metabolism). The discovery of the presence of IREs in a number of other mRNAs has extended our knowledge of the influence of the IRE/IRP regulatory network to new metabolic pathways, and it has been recently learned that an increasing number of agents and physiopathological conditions impinge on the IRE/IRP system. This review focuses on recent findings concerning the IRP-mediated regulation of iron homeostasis, its alterations in disease, and new research directions to be explored in the near future.

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P4‐187: Iron regulatory protein 2 is involved in brain copper homeostasis

Cited by 4 publications

References 32 publications

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

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

Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

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