Aceruloplasminemia: An Inherited Neurodegenerative Disease with Impairment of Iron Homeostasis

Xu, Xueying; Pin, Sokhon; Gathinji, Muraya; Fuchs, Ralph; Harris, Z. Leah

doi:10.1196/annals.1306.024

Cited by 146 publications

(96 citation statements)

References 32 publications

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“…A slow time course of the neuropathology is also seen in humans with aceruloplasminemia (Miyajima et al, 1987;Xu et al, 2004). Because GPI-Cp is essential for iron efflux from astrocytes, the slow accumulation of iron in Cp Ϫ/Ϫ mice and people with aceruloplasminemia suggest that there are either additional mechanisms in vivo that help clear iron from astrocytes, albeit not completely efficiently, or that the turnover of iron in the CNS is very slow.…”

Section: Role Of Astrocytes In Iron Trafficking In the Cnsmentioning

confidence: 97%

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Jeong¹,

David²

2006

J. Neurosci.

133

145

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Iron is essential for a variety of cellular functions, but its levels and bioavailability must be tightly regulated because of its toxic redox activity. A number of transporters, binding proteins, reductases, and ferroxidases help maintain iron homeostasis to prevent cell damage. The multi-copper ferroxidase ceruloplasmin (Cp) converts toxic ferrous iron to its nontoxic ferric form and is required for iron efflux from cells. Absence of this enzyme in humans leads to iron accumulation and neurodegeneration in the CNS. Here we report on the changes that occur in the cerebellum of Cp null (Cp Ϫ/Ϫ ) mice with aging. We show that iron accumulation, which is reflected in increased ferritin expression, occurs mainly in astrocytes by 24 months in Cp Ϫ/Ϫ mice and is accompanied by a significant loss of these cells. In contrast, Purkinje neurons and the large neurons in the deep nuclei of Cp Ϫ/Ϫ mice do not accumulate iron but express high levels of the iron importer divalent metal transporter 1, suggesting that these cells may be iron deprived. This is also accompanied by a significant reduction in the number of Purkinje neurons. These data suggest that astrocytes play a central role in the acquisition of iron from the circulation and that two different mechanisms underlie the loss of astrocytes and neurons in Cp Ϫ/Ϫ mice. These findings provide a better understanding of the degenerative changes seen in humans with aceruloplasminemia and have implications for normal aging and neurodegenerative diseases in which iron accumulation occurs.

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Section: Role Of Astrocytes In Iron Trafficking In the Cnsmentioning

confidence: 97%

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Jeong¹,

David²

2006

J. Neurosci.

133

145

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“…Similarly, total liver iron was increased in IRP1 ϩ/Ϫ IRP2 Ϫ/Ϫ mice relative to WT, which again illustrates the complexity of assessing iron status. There are several other diseases in which significant tissue iron overload occurs in conjunction with anemia, including aceruloplasminemia 50 and atransferrinemia, 51 but in these diseases, tissue iron overload is generally more profound when assessed by staining, ashing, and nonheme iron assays. Like atransferrinemic mice, IRP2 Ϫ/Ϫ mice develop hepatic iron overload and bone marrow macrophage iron deficiency.…”

Section: Discussionmentioning

confidence: 99%

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2

Cooperman

Meyron-Holtz

Olivierre-Wilson

et al. 2005

Blood

203

198

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Iron-regulatory proteins (IRPs) 1 and 2 posttranscriptionally regulate expression of transferrin receptor (TfR), ferritin, and other iron metabolism proteins. Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues. Despite this misregulation, there are no apparent pathologic consequences in tissues such as the liver and kidney. However, in the central nervous system, evidence of abnormal iron metabolism in IRP2 ؊/؊ mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss. Here, we report that ablation of IRP2 results in ironlimited erythropoiesis. TfR expression in erythroid precursors of IRP2 ؊/؊ mice is reduced, and bone marrow iron stores are absent, even though transferrin saturation levels are normal. Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRPdependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2 ؊/؊ erythroid cells. IRP2 IntroductionIron functions as an indispensable cofactor for numerous enzymes and proteins in mammals, and regulation of iron uptake and distribution within animals is accordingly highly regulated. 1,2 Intestinal iron absorption and tissue iron storage are optimized to deliver the iron needed for numerous metabolic processes, including heme synthesis. The recently identified peptide hormone, hepcidin, is responsible for appropriately coordinating intestinal iron uptake and macrophage iron release to meet the needs of the organism and to maintain normal serum transferrin saturation levels. 3 In most tissues, the circulating pool of diferric transferrin serves as the major source of iron for individual cells. When diferric transferrin (Tf) binds to transferrin receptors (TfRs), the Tf-TfR complex internalizes in endosomes, where acidification facilitates release of free iron, 4 and the membrane iron transporter divalent metal transporter 1 (DMT1) (SLC11A2) transports iron into the cytosol. 5,6 In the cytosol, iron is incorporated into iron proteins or transported to cellular organelles, and excess cytosolic iron is sequestered and stored by ferritin. 6,7 Cells regulate expression of ferritin and TfR to optimize cytosolic iron levels. When cells are iron depleted, they increase TfR expression and uptake of transferrinbound iron, while they simultaneously decrease expression of ferritin and iron sequestration. Proteins known as iron regulatory proteins (IRPs) coordinately regulate expression of TfR, ferritin, and numerous other iron metabolism proteins. IRP1 and IRP2 are homologous genes that monitor cytosolic iron levels. When cells are iron depleted, IRPs bind to RNA motifs known as iron-responsive elements (IREs) within transcripts that encode iron metabolism proteins (reviewed in Rouault and Klausner 1 ; and Hentze et al 2 ). IREs are found in numerous transcripts, including ferritin H-and L-chains, TfR1, 7 erythrocyti...

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“…Patients develop diabetes mellitus, retinal degeneration, ataxia, and dementia late in life. 122 A mild-to-moderate degree of anemia with low serum iron and elevated serum ferritin is a constant feature. Aceruloplasminemia has been described mainly in Japanese patients and rarely in whites.…”

Section: Hereditary Atransferrinemiamentioning

confidence: 99%

Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis

Iolascon¹,

Falco²,

Beaumont³

2009

Haematologica

134

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© F e r r a t a S t o r t i F o u n d a t i o nAIn this paper we will review the new information available on the iron acquisition pathway by developing erythrocytes and its regulation, and we will consider only inherited microcytosis due to heme synthesis or to iron metabolism defects. Iron and erythropoiesis Iron acquisition pathway in erythroid cellsDeveloping erythroid cells in the bone marrow acquire iron from the plasma iron-transferrin (Tf) complex, through the transferrin receptor (TfR) mediated pathway ( Figure 1). All proliferating cells express transferrin receptors on their cell surface at levels varying from 10 3 to 10 5 molecules per cell. Erythroid precursors, which have an extraordinary requirement for iron to allow for production of hemoglobin, may have over 10 6 transferrin receptors per cell.3 The transferrin-Fe(III) complex in plasma is transported into cells principally through transferrin receptor 1 (TfR1), which is expressed on all dividing cells and is particularly abundant on erythroid precursors. TfR2, encoded by a different gene, is expressed primarily in the liver and binds the transferrin-Fe(III) complex at a much lower affinity than TfR1 and appears to be a signaling molecule rather than an iron transporter. 4 At the pH of the cell surface, TfR1 binds only diferric transferrin. The Tf-Fe(III)/TfR1 complex is internalized into a clathrin-coated pit that, assisted by an adaptor protein complex designated AP-2, 5 rapidly matures to a proton-pumping, pH-lowering endosome. At the lowered pH, iron is released from Tf and subsequently reduced to Fe(II) and transported across the endosomal membrane by Divalent Metal Transporter 1 (DMT1).6 DMT1/Nramp2, a member of the Natural Resistance-Associated-Macrophage Protein (Nramp) family, is a proton-coupled divalent metal transporter found at the plasma membrane and in endosomes of cells of both the duodenum and peripheral tissues. Iron-depleted Tf is then returned to the cell surface where, again encountering a pH of 7.4, the protein is released for another cycle of iron transport. Recently, Steap3 (6-transmembrane epithelial antigen of the prostate 3), an endosomal ferrireductase that facilitates Tf-mediated uptake of iron in erythroid precursors has been identified. 8Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tfbound iron uptake. Erythroid cells from mice deficient in Steap3 (nm1054) are defective in Tf-dependent iron uptake, resulting in a hypochromic, microcytic anemia typical of iron deficiency 9 whereas overexpression of Steap3 stimulates the reduction of iron. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells. However, nml054 and Steap3 −/− erythroid precursors retain some residual ferrireductase as well as iron uptake activity, indicating that there are other ways of reducing iron in the Tf-cycle endosome and/or that there are other endosomal iron transporters that are not res...

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Aceruloplasminemia: An Inherited Neurodegenerative Disease with Impairment of Iron Homeostasis

Cited by 146 publications

References 32 publications

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2

Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis

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