Functional roles of transferrin in the brain

Leitner, Dominique F.; Connor, James R.

doi:10.1016/j.bbagen.2011.10.016

Cited by 137 publications

(125 citation statements)

References 159 publications

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“…Apotransferrin binds with high affinity to iron in circulation, forming holotransferrin, which binds to TfR1 expressed by endothelial cells in the blood-brain barrier and epithelial cells in the BCB [43]. The holotransferrin complex is then endocytosed into the endothelial/epithelial cells, ending up in the endosomal/lysosomal compartment, where the acid environment dissociates iron from holotransferrin, followed by iron transport to the cytosol [44]. Once iron is released, apotransferrin is then recycled to the cell membrane.…”

Section: Resultsmentioning

confidence: 99%

Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

et al. 2015

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.

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Section: Resultsmentioning

confidence: 99%

Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

et al. 2015

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“…Meanwhile, iron can bind to a series of small ligands with low molecular weight, such as citrate and ascorbate ions, released from astrocytes, which is called non-transferrin bound iron (NTBI). Investigator finds the presence of NTBI in the extracellular fluids [28] and the affinity of iron to small ligands is considerably smaller than that to transferrin [29], leading to a proportion of free iron in the extracellular space. Moreover, ferroportin, which mediates the export pathway and allows ferrous iron to be transported out of the cell [30], has been identified in both neurons [31] and astrocytes [32], contributing to ferrous iron in the extracellular space.…”

Section: Discussionmentioning

confidence: 99%

Role and Mechanism of Microglial Activation in Iron-Induced Selective and Progressive Dopaminergic Neurodegeneration

et al. 2013

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Parkinson’s disease (PD) patients have excessive iron depositions in substantia nigra (SN). Neuroinflammation characterized by microglial activation is pivotal for dopaminergic neurodegeneration in PD. However, the role and mechanism of microglial activation in iron-induced dopaminergic neurodegeneration in SN remain unclear yet. This study aimed to investigate the role and mechanism of microglial β-nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) activation in iron-induced selective and progressive dopaminergic neurodegeneration. Multiple primary midbrain cultures from rat, NOX2+/+ and NOX2−/− mice were used. Dopaminergic neurons, total neurons, and microglia were visualized by immunostainings. Cell viability was measured by MTT assay. Superoxide (O2·−) and intracellular reactive oxygen species (iROS) were determined by measuring SOD-inhibitable reduction of tetrazolium salt WST-1 and DCFH-DA assay. mRNA and protein were detected by real-time PCR and Western blot. Iron induces selective and progressive dopaminergic neurotoxicity in rat neuron–microglia–astroglia cultures and microglial activation potentiates the neurotoxicity. Activated microglia produce a magnitude of O2·− and iROS, and display morphological alteration. NOX2 inhibitor diphenylene iodonium protects against iron-elicited dopaminergic neurotoxicity through decreasing microglial O2·− generation, and NOX2−/− mice are resistant to the neurotoxicity by reducing microglial O2·− production, indicating that iron-elicited dopaminergic neurotoxicity is dependent of NOX2, a O2·−-generating enzyme. NOX2 activation is indicated by the increased mRNA and protein levels of subunits P47 and gp91. Molecules relevant to NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-ΚBP65 as their mRNA and protein levels are enhanced by NOX2 activation. Iron causes selective and progressive dopaminergic neurodegeneration, and microglial NOX2 activation potentiates the neurotoxicity. PKC-σ, P38, ERK1/2, JNK, and NF-ΚBP65 are the potential molecules relevant to microglial NOX2 activation.

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“…In contrast, metals such as lead, mercury or zinc which are mainly trapped in red blood cells or incorporated in macromolecular proteins, do not penetrate to the same extent into the CSF, not even in Skogholt disease patients. With regard to a further penetration of Fe species into the cerebral white matter of these patients, it is relevant to note that oligodendrocytes and myelin are rich in transferrin receptors [23], rendering white matter susceptible to Fe overload. Furthermore, localized brain Fe accumulations, as observed in MS, may be implicated in the pathogenesis of demyelination [24][25][26][27][28][29][30].…”

Section: By What Mechanisms Are Iron and Copper Transferred From Bloomentioning

confidence: 99%

Iron and copper in progressive demyelination – New lessons from Skogholt's disease

Aspli

Flaten

Roos

et al. 2015

Journal of Trace Elements in Medicine and Biology

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Functional roles of transferrin in the brain

Cited by 137 publications

References 159 publications

Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

Role and Mechanism of Microglial Activation in Iron-Induced Selective and Progressive Dopaminergic Neurodegeneration

Iron and copper in progressive demyelination – New lessons from Skogholt's disease

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