UNIPROT:P02794 - FACTA Search

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Query: UNIPROT:P02794 (ferritin)
17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian brains contain low levels of the Alzheimer amyloid precursor variants (AAPPs) and the normal form of the scrapie agent protease-resistant protein (PrPc); however, their mRNAs are readily detectable. To understand these discrepancies we have investigated some aspects of the translational regulation of these mRNAs. An accurate blot-hybridization procedure was developed to measure absolute amounts of mRNA. Rat brain contains the following mRNA levels (ng/g tissue) AAPP(695), 170; AAPP(751/770), 63; PrPc, 144; actin, 615; glyceraldehyde-3-phosphate dehydrogenase (G3PDH), 359; ferritin, 148. The method was also used to determine the distribution of mRNAs between translationally active polysomes and translationally inactive ribonucleoprotein protein particles (mRNPs). More than 90% of G3PDH and actin mRNAs were associated with polysomal RNA; whereas, ferritin light chain mRNA was predominantly (90%) in mRNP RNA. The degree of cross-contamination of mRNPs with polysomes was less than 10%. Probes specific for the scrapie PrP protein and the AAPP(695) splice junction revealed that 70% of these mRNAs were associated with polysomes. One-half of AAPP(751/770) mRNAs (which comprise 20-30% of all AAPP mRNA in brain) were found in polysomes. We conclude therefore that both scrapie and AAPP mRNAs are subject to translational regulation in rat brain. Evidence from in vitro translational experiments confirm the message distribution determined by blot hybridization and corroborate the hypothesis that AAPP is subject to partial post-transcriptional regulation. Nevertheless, the low tissue levels of AAPP and PrPc must result primarily from their relatively rapid turnover.
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PMID:Distribution and activity of alternatively spliced Alzheimer amyloid peptide precursor and scrapie PrP mRNAs on rat brain polysomes. 168 Mar 10

Foodborne transmission of bovine spongiform encephalopathy (BSE) to humans as variant Creutzfeldt-Jakob disease (CJD) has affected over 100 individuals, and probably millions of others have been exposed to BSE-contaminated food substances. Despite these obvious public health concerns, surprisingly little is known about the mechanism by which PrP-scrapie (PrP(Sc)), the most reliable surrogate marker of infection in BSE-contaminated food, crosses the human intestinal epithelial cell barrier. Here we show that digestive enzyme (DE) treatment of sporadic CJD brain homogenate generates a C-terminal fragment similar to the proteinase K-resistant PrP(Sc) core of 27-30 kDa implicated in prion disease transmission and pathogenesis. Notably, DE treatment results in a PrP(Sc)-protein complex that is avidly transcytosed in vesicular structures across an in vitro model of the human intestinal epithelial cell barrier, regardless of the amount of endogenous PrP(C) expression. Unexpectedly, PrP(Sc) is cotransported with ferritin, a prominent component of the DE-treated PrP(Sc)-protein complex. The transport of PrP(Sc)-ferritin is sensitive to low temperature, brefeldin-A, and nocodazole treatment and is inhibited by excess free ferritin, implicating a receptor- or transporter-mediated pathway. Because ferritin shares considerable homology across species, these data suggest that PrP(Sc)-associated proteins, in particular ferritin, may facilitate PrP(Sc) uptake in the intestine from distant species, leading to a carrier state in humans.
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PMID:Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: implications for species barrier in prion uptake from the intestine. 1560 34

Prion diseases are characterized by the conversion of the normal cellular prion protein PrP(C) into a pathogenic isoform, PrP(Sc). The mechanisms involved in neuronal cell death in prion diseases are largely unknown, but accumulating evidence has demonstrated oxidative impairment along with metal imbalances in scrapie-infected brains. In this study, we report changes in cellular iron metabolism in scrapie-infected mouse neuroblastoma N2a cells (ScN2a). We detected twofold lower total cellular iron and calcein-chelatable cytosolic labile iron pool (LIP) in ScN2a cells as compared to the N2a cells. We also measured in ScN2a cells significantly lower activities of iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively), regulators of cellular iron by sensing cytosolic free iron levels and controlling posttranscriptionally the expression of the major iron transport protein transferrin receptor 1 (TfR1) and the iron sequestration protein ferritin. IRP1 and IRP2 protein levels were decreased by 40% and 50%, respectively, in ScN2a cells. TfR1 protein levels were fourfold reduced and ferritin levels were threefold reduced in ScN2a cells. TfR1 and ferritin mRNA levels were significantly reduced in ScN2a cells. ScN2a cells responded normally to iron and iron chelator treatment with respect to the activities of IRP1 and IRP2, and biosynthesis of TfR1 and ferritin. However, the activities of IRP1 and IRP2, and protein levels of TfR1 and ferritin, were still significantly lower in iron-depleted ScN2a cells as compared to the N2a cells, suggesting lower need for iron in ScN2a cells. Our results demonstrate that scrapie infection leads to changes in cellular iron metabolism, affecting both total cellular and cytosolic free iron, and the activities and expression of major regulators of cellular iron homeostasis.
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PMID:Changed iron regulation in scrapie-infected neuroblastoma cells. 1571 Feb 43

This paper exposes the flaws in the conventional consensus on the origins of transmissible spongiform encephalopathies (TSEs) which decrees that the protein-only misfolded 'prion' represents the primary aetiological transmissible agent, and then reviews/presents the emerging data which indicates that environmental exposure to metal microcrystal pollutants (sourced from munitions, etc.) represents the heat resistant, transmissible nucleating agents which seed the metal-prion protein (PrP)-ferritin fibril crystals that cause TSE. Fresh analytical data is presented on the levels of metals in ecosystems which support populations affected by clusters of variant Creutzfeldt-Jacob disease (vCJD), sporadic/familial CJD, and the scrapie types of TSE that have emerged in the UK, Sicily, Sardinia, Calabria and Japan. This data further substantiates the abnormal geochemical template (e.g., elevated strontium (Sr), barium (Ba) and silver (Ag)) which was observed as a common hallmark of the TSE cluster ecosystems across North America, thereby supporting the hypothesis that these microcrystals serve as the piezoelectrion nucleators which seed the growth/multireplication of the aberrant metal-PrP-ferritin fibril features which characterise the neuropathology of the TSE diseased brain. A secondary pathogenic mechanism entails the inactivation of the sulphated proteoglycans which normally regulate the mineralisation process. This can be induced by a rogue metal mediated chelation of free sulphur, or by contamination with organo-sulphur pollutants that substitute at natural sulphur bonds, or via a mutation to the S-proteoglycan cell line; thereby enabling the aberrant overgrowth of rogue fibril crystal formations that possess a piezoelectric capacity which compromises the ability of the contaminated individual to process incoming acoustic/tactile pressure waves in the normal way. The crystals transduce incoming sonic energy into electrical energy, which, in turn, generates magnetic fields on the crystal surfaces that initiate chain reactions of free radical mediated spongiform neurodegeneration. Metal microcrystal nucleating agents provide a group of plausible aetiological candidates that explain the unique properties of the TSE causal agent - such as heat resistance, transmissibility, etc. - which the protein-only prion model fails to fulfill. This paper also discusses the possible nutritional measures that could best be adopted by populations living in high risk TSE ecosystems; as a means of preventing the successful implantation of these rogue microcrystals and their consequent hypermineralisation of the soft tissues within the CNS.
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PMID:Metal microcrystal pollutants: the heat resistant, transmissible nucleating agents that initiate the pathogenesis of TSEs? 1590 37

Converging evidence leaves little doubt that a change in the conformation of prion protein (PrP(C)) from a mainly alpha-helical to a beta-sheet rich PrP-scrapie (PrP(Sc)) form is the main event responsible for prion disease associated neurotoxicity. However, neither the mechanism of toxicity by PrP(Sc), nor the normal function of PrP(C) is entirely clear. Recent reports suggest that imbalance of iron homeostasis is a common feature of prion infected cells and mouse models, implicating redox-iron in prion disease pathogenesis. In this report, we provide evidence that PrP(C) mediates cellular iron uptake and transport, and mutant PrP forms alter cellular iron levels differentially. Using human neuroblastoma cells as models, we demonstrate that over-expression of PrP(C) increases intra-cellular iron relative to non-transfected controls as indicated by an increase in total cellular iron, the cellular labile iron pool (LIP), and iron content of ferritin. As a result, the levels of iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) are decreased, and expression of iron storage protein ferritin is increased. The positive effect of PrP(C) on ferritin iron content is enhanced by stimulating PrP(C) endocytosis, and reversed by cross-linking PrP(C) on the plasma membrane. Expression of mutant PrP forms lacking the octapeptide-repeats, the membrane anchor, or carrying the pathogenic mutation PrP(102L) decreases ferritin iron content significantly relative to PrP(C) expressing cells, but the effect on cellular LIP and levels of Tf, TfR, and ferritin is complex, varying with the mutation. Neither PrP(C) nor the mutant PrP forms influence the rate or amount of iron released into the medium, suggesting a functional role for PrP(C) in cellular iron uptake and transport to ferritin, and dysfunction of PrP(C) as a significant contributing factor of brain iron imbalance in prion disorders.
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PMID:Prion protein modulates cellular iron uptake: a novel function with implications for prion disease pathogenesis. 1921 44

Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrP(Sc)), a beta-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrP(C)). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease-affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)-affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrP(Sc) as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrP(Sc)-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrP(Sc)-ferritin complexes induces a state of iron bio-insufficiency in prion disease-affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These data implicate redox-iron in prion disease-associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis.
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PMID:Abnormal brain iron homeostasis in human and animal prion disorders. 1928 67

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders characterized by the accumulation in the CNS of a pathological conformer (PrP(TSE)) of the host-encoded cellular prion protein (PrP(C)). PrP(TSE) has a central role in the pathogenesis of the disease but other factors are likely involved in the pathological process. In this work we employed a multi-step proteomic approach for the identification of proteins that co-purify with the protease-resistant core of PrP(TSE) (PrP27-30) extracted from brains of hamsters with experimental scrapie. We identified ferritin, calcium/calmodulin-dependent protein kinase alpha type II, apolipoprotein E, and tubulin as the major components associated with PrP27-30 but also trace amounts of actin, cofilin, Hsp90alpha, the gamma subunit of the T-complex protein 1, glyceraldehyde 3-phosphate dehydrogenase, histones, and keratins. Whereas some of these proteins (tubulin and ferritin) are known to bind PrP, other proteins (calcium/calmodulin-dependent protein kinase alpha type II, Hsp90alpha) may associate with PrP(TSE) fibrils during disease. Apolipoprotein E and actin have been previously observed in association with PrP(TSE), whereas cofilin and actin were shown to form abnormal rods in the brain of patients with Alzheimer disease. The roles of these proteins in the development of brain lesions are still unclear and further work is needed to explain their involvement in the pathogenesis of TSEs.
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PMID:Proteomic profiling of PrP27-30-enriched preparations extracted from the brain of hamsters with experimental scrapie. 1963 40

The spread of Chronic Wasting Disease (CWD) in the deer and elk population has caused serious public health concerns due to its potential to infect farm animals and humans. Like other prion disorders such a sporadic Creutzfeldt-Jakob-disease of humans and Mad Cow Disease of cattle, CWD is caused by PrP-scrapie (PrPSc), a beta-sheet rich isoform of a normal cell surface glycoprotein, the prion protein (PrPC). Since PrPSc is sufficient to cause infection and neurotoxicity if ingested by a susceptible host, it is important to understand the mechanism by which it crosses the stringent epithelial cell barrier of the small intestine. Possible mechanisms include co-transport with ferritin in ingested food and uptake by dendritic cells. Since ferritin is ubiquitously expressed and shares considerable homology among species, co-transport of PrPSc with ferritin can result in cross-species spread with deleterious consequences. We have used a combination of in vitro and in vivo models of intestinal epithelial cell barrier to understand the role of ferritin in mediating PrPSc uptake and transport. In this report, we demonstrate that PrPSc and ferritin from CWD affected deer and elk brains and scrapie from sheep resist degradation by digestive enzymes, and are transcytosed across a tight monolayer of human epithelial cells with significant efficiency. Likewise, ferritin from hamster brains is taken up by mouse intestinal epithelial cells in vivo, indicating that uptake of ferritin is not limited by species differences as described for prions. More importantly, the iron content of ferritin determines its efficiency of uptake and transport by Caco-2 cells and mouse models, providing insight into the mechanism(s) of ferritin and PrPSc uptake by intestinal epithelial cells.
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PMID:Iron content of ferritin modulates its uptake by intestinal epithelium: implications for co-transport of prions. 2042 7

Prion disease associated neurotoxicity is mainly attributed to PrP-scrapie (PrP(Sc)), the disease associated isoform of a normal protein, the prion protein (PrP(C)). Participation of other proteins and processes is suspected, but their identity and contribution to the pathogenic process is unclear. Emerging evidence implicates imbalance of brain iron homeostasis as a significant cause of prion disease-associated neurotoxicity. The underlying cause of this change, however, remains unclear. We demonstrate that iron is sequestered in heat and SDS-stable protein complexes in sporadic-Creutzfeldt-Jakob-disease (sCJD) brains, creating a phenotype of iron deficiency. The underlying cause is change in the characteristics of ferritin, an iron storage protein that becomes aggregated, detergent-insoluble, and partitions with denatured ferritin using conventional methods of ferritin purification. A similar phenotype of iron deficiency is noted in the lumbar spinal cord (SC) tissue of scrapie infected hamsters, a site unlikely to be affected by massive neuronal death and non-specific iron deposition. As a result, the iron uptake protein transferrin (Tf) is upregulated in scrapie infected SC tissue, and increases with disease progression. A direct correlation between Tf and PrP(Sc) suggests sequestration of iron in dysfunctional ferritin that either co-aggregates with PrP(Sc) or is rendered dysfunctional by PrP(Sc) through an indirect process. Surprisingly, amplification of PrP(Sc)in vitro by the protein-misfolding-cyclic-amplification (PMCA) reaction using normal brain homogenate as substrate does not increase the heat and SDS-stable pool of iron even though both PrP(Sc) and ferritin aggregate by this procedure. These observations highlight important differences between PrP(Sc)-protein complexes generated in vivo during disease progression and in vitro by the PMCA reaction, and the significance of these complexes in PrP(Sc)-associated neurotoxicity.
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PMID:Change in the characteristics of ferritin induces iron imbalance in prion disease affected brains. 2218 91

Excess circulating iron is stored in the liver, and requires reduction of non-Tf-bound iron (NTBI) and transferrin (Tf) iron at the plasma membrane and endosomes, respectively, by ferrireductase (FR) proteins for transport across biological membranes through divalent metal transporters. Here, we report that prion protein (PrP(C)), a ubiquitously expressed glycoprotein most abundant on neuronal cells, functions as a FR partner for divalent-metal transporter-1 (DMT1) and ZIP14. Thus, absence of PrP(C) in PrP-knock-out (PrP(-/-)) mice resulted in markedly reduced liver iron stores, a deficiency that was not corrected by chronic or acute administration of iron by the oral or intraperitoneal routes. Likewise, preferential radiolabeling of circulating NTBI with (59)Fe revealed significantly reduced uptake and storage of NTBI by the liver of PrP(-/-) mice relative to matched PrP(+/+) controls. However, uptake, storage, and utilization of ferritin-bound iron that does not require reduction for uptake were increased in PrP(-/-) mice, indicating a compensatory response to the iron deficiency. Expression of exogenous PrP(C) in HepG2 cells increased uptake and storage of ferric iron (Fe(3+)), not ferrous iron (Fe(2+)), from the medium, supporting the function of PrP(C) as a plasma membrane FR. Coexpression of PrP(C) with ZIP14 and DMT1 in HepG2 cells increased uptake of Fe(3+) significantly, and surprisingly, increased the ratio of N-terminally truncated PrP(C) forms lacking the FR domain relative to full-length PrP(C). Together, these observations indicate that PrP(C) promotes, and possibly regulates, the uptake of NTBI through DMT1 and Zip14 via its FR activity. Implications of these observations for neuronal iron homeostasis under physiological and pathological conditions are discussed.
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PMID:Prion protein functions as a ferrireductase partner for ZIP14 and DMT1. 2586 12

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