Mice with hepcidin‐resistant ferroportin accumulate iron in the retina

Theurl, Milan; Song, Delu; Clark, Esther; Sterling, Jacob; Grieco, Steve; Altamura, Sandro; Galy, Bruno; Hentze, Matthias W.; Muckenthaler, Martina U.; Dunaief, Joshua L.

doi:10.1096/fj.15-276758

Cited by 33 publications

(26 citation statements)

References 34 publications

(50 reference statements)

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“…Following counterstaining with hematoxylin, the sections were mounted in permount and observed. For immunostaining with fluorescent secondary antibodies, deparaffinized and rehydrated sections were subjected to antigen retrieval by heating to 97°C in the presence of 25mM tris-1mM EDTA (pH 8.5) for 40 min [63]. Subsequently, sections were blocked in 1% BSA, washed, and incubated with the desired primary and secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

Baksi

Tripathi

Singh

2016

Free Radical Biology and Medicine

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Aggregation of α-synuclein (α-syn) in neurons of the substantia nigra is diagnostic of Parkinson’s disease (PD), a neuro-motor disorder with prominent visual symptoms. Here, we demonstrate that α-syn, the principal protein involved in the pathogenesis of PD, is expressed widely in the neuroretina, and facilitates the uptake of transferrin-bound iron (Tf-Fe) by retinal pigment epithelial (RPE) cells that form the outer blood-retinal barrier. Absence of α-syn in knock-out mice (α-syn−/−) resulted in down-regulation of ferritin in the neuroretina, indicating depletion of cellular iron stores. A similar phenotype of iron deficiency was observed in the spleen, femur, and brain tissue of α-syn−/− mice, organs that utilize mainly Tf-Fe for their metabolic needs. The liver and kidney, organs that take up significant amounts of non-Tf-bound iron (NTBI), showed minimal change. Evaluation of the underlying mechanism in the human RPE47 cell line suggested a prominent role of α-syn in the uptake of Tf-Fe by modulating the endocytosis and recycling of transferrin (Tf)/transferrin-receptor (TfR) complex. Down-regulation of α-syn in RPE cells by RNAi resulted in the accumulation of Tf/TfR complex in common recycling endosomes (CREs), indicating disruption of recycling to the plasma membrane. Over-expression of exogenous α-syn in RPE cells, on the other hand, up-regulated ferritin and TfR expression. Interestingly, exposure to exogenous iron increased membrane association and co-localization of α-syn with TfR, supporting its role in iron uptake by the Tf/TfR complex. Together with our observations indicating basolateral expression of α-syn and TfR on RPE cells in vivo, this study reveals a novel function of α-syn in the uptake of Tf-Fe by the neuroretina. It is likely that retinal iron dyshomeostasis due to impaired or altered function of α-syn contributes to the visual symptoms associated with PD.

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Section: Methodsmentioning

confidence: 99%

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

Baksi

Tripathi

Singh

2016

Free Radical Biology and Medicine

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“… 18 If Müller cells are the predominant producers of retinal hepcidin, a decrease in the number of functional Müller cells may lead to a decrease in hepcidin production. Our lab has previously demonstrated that there is retinal iron accumulation in mice that have a hepcidin-resistant mutant form of Fpn 19 and in hepcidin knockout mice. 20 These data suggest that Müller cell loss, and a potential decrease in hepcidin production, may lead to the same iron accumulation phenotype.…”

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confidence: 99%

Conditional Müller Cell Ablation Leads to Retinal Iron Accumulation

Baumann

Sterling

Song

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeRetinal iron accumulation is observed in a wide range of retinal degenerative diseases, including AMD. Previous work suggests that Müller glial cells may be important mediators of retinal iron transport, distribution, and regulation. A transgenic model of Müller cell loss recently demonstrated that primary Müller cell ablation leads to blood–retinal barrier leakage and photoreceptor degeneration, and it recapitulates clinical features observed in macular telangiectasia type 2 (MacTel2), a rare human disease that features Müller cell loss. We used this mouse model to determine the effect of Müller cell loss on retinal iron homeostasis.MethodsChanges in total retinal iron levels after Müller cell ablation were measured using inductively coupled plasma mass spectrometry. Corresponding changes in the expression of iron flux and iron storage proteins were determined using quantitative PCR, Western analysis, and immunohistochemistry.ResultsMüller cell loss led to blood–retinal barrier breakdown and increased iron levels throughout the neurosensory retina. There were corresponding changes in mRNA and/or protein levels of ferritin, transferrin receptor, ferroportin, Zip8, and Zip14. There were also increased iron levels within the RPE of retinal sections from a patient with MacTel2 and both RPE and neurosensory retina of a patient with diabetic retinopathy, which, like MacTel2, causes retinal vascular leakage.ConclusionThis study shows that Müller cells and the blood–retinal barrier play pivotal roles in the regulation of retinal iron homeostasis. The retinal iron accumulation resulting from blood–retinal barrier dysfunction may contribute to retinal degeneration in this model and in diseases such as MacTel2 and diabetic retinopathy.

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“…In this context, mice with hepcidinresistant ferroportin have been shown to accumulate iron in the retina. 26 Humans with aceruloplasminemia develop RPE iron overload. 27 These mechanisms may also be disrupted with age.…”

Section: Resultsmentioning

confidence: 99%

Iron accumulates in the primate choroid of the eye with aging as revealed with synchrotron X-ray fluorescence microscopy

Ugarte

Geraki

Jeffery³

2016

Metallomics

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Aging leads to an increase in iron-loaded cellular structures in the choroid of the eye. This study was carried out to determine the distribution and content of iron, zinc and copper in the macular retina, choroid and retrobulbar optic nerve of young (4-5 years, n = 3) and aged (15-16 years, n = 5) male non-human primates, Macaca fascicularis, whose ocular anatomy is similar to humans. Thirty μm-thick tissue sections were analysed with synchrotron X-ray fluorescence and stained histologically for iron deposition. Quantitative measurements showed high levels of iron, zinc and copper in the choroid and retinal pigment epithelium in the macular area and arachnoid layer in the retrobulbar optic nerve. In aged animals compared to young ones, there was an increase in iron in the choroid with larger deposits and iron-loaded cellular structures. Iron-accumulation within these cellular structures may contribute to choroidal function impairment in aging and age-related macular degeneration.

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Mice with hepcidin‐resistant ferroportin accumulate iron in the retina

Cited by 33 publications

References 34 publications

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease

Conditional Müller Cell Ablation Leads to Retinal Iron Accumulation

Iron accumulates in the primate choroid of the eye with aging as revealed with synchrotron X-ray fluorescence microscopy

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