Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dual role of cellular prion protein in normal host and Alzheimer's disease.

ABSTRACT: Using PrPC-knockout cell lines, it has been shown that the inhibition of apoptosis through STI1 is mediated by PrPC-dependent SOD activation. Antioxidant PrPC may contribute to suppression of inflammasome activation. PrPC is functionally involved in copper metabolism, signal transduction, neuroprotection, and cell maturation. Recently several reports have shown that PrPC participates in trans-membrane signaling processes associated with hematopoietic stem cell replication and neuronal differentiation. In another role, PrPC also tends to function as a neurotoxic protein. Aβ oligomer, which is associated with neurodegeneration in Alzheimer's disease (AD), has also been reported to act as a ligand of PrPC. However, the physiological role of PrPC as an Aβ42-binding protein is not clear. Actually, PrPC is critical in Aβ42-mediated autophagy in neurons. PrPC shows a beneficial role in lipid rafts to promote autophagy. Further search for PrPC-interaction molecules using Prnp-/- mice and various types of Prnp-/- cell lines under various conditions may elucidate other important PrPC important functions.

SUBMITTER: Onodera T

PROVIDER: S-EPMC5489426 | biostudies-other | 2017

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease.

Project description:Soluble oligomers of amyloid-beta (Aβo) are implicated by biochemical and genetic evidence as a trigger for Alzheimer's disease (AD) pathophysiology. A key step is Aβo interaction with the neuronal surface to initiate a cascade of altered signal transduction leading to synaptic dysfunction and damage. This review discusses neuronal cell surface molecules with high affinity selectively for oligomeric disease-associated states of Aβ, with a particular focus on the role of cellular prion protein (PrPC) in this process. Additional receptors may contribute to mediation of Aβo action, but PrPC appears to play a primary role in a number of systems. The specificity of binding, the genetic necessity in mouse models of disease and downstream signaling pathways are considered. Signal transduction downstream of Aβo complexes with PrPC involves metabotropic glutamate receptor 5 (mGluR5), Fyn kinase and Pyk2 kinase, with deleterious effects on synaptic transmission and maintenance. Current data support the hypothesis that a substantial portion of Aβo toxicity in AD is mediated after initial interaction with PrPC on the neuronal surface. As such, the interaction of Aβo with PrPC is a potential therapeutic intervention site for AD.

| S-EPMC5303667 | biostudies-literature

Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease.

Project description:Alzheimer's disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer's disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-? oligomers, by mouse brain Alzheimer's disease transgenes or by human Alzheimer's disease pathology. Amyloid-? oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp-Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer's disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer's disease pathogenesis, and the complex is a potential target for disease-modifying intervention.

| S-EPMC4840505 | biostudies-literature

Cellular Prion Protein as a Receptor of Toxic Amyloid-β42 Oligomers Is Important for Alzheimer's Disease.

Project description:The pathological features of Alzheimer's disease (AD) include senile plaques induced by amyloid-β (Aβ) protein deposits, neurofibrillary tangles formed by aggregates of hyperphosphorylated tau proteins and neuronal cell loss in specific position within the brain. Recent observations have suggested the possibility of an association between AD and cellular prion protein (PrP C ) levels. PrP C is a high affinity receptor for oligomeric Aβ and is important for Aβ-induced neurotoxicity and thus plays a critical role in AD pathogenesis. The determination of the relationship between PrP C and AD and the characterization of PrP C binding to Aβ will facilitate the development of novel therapies for AD.

| S-EPMC6682659 | biostudies-literature

Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists.

Project description:Cellular prion protein (PrPC) binds the scrapie conformation of PrP (PrPSc) and oligomeric β-amyloid peptide (Aβo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer's disease (AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrPC interaction with Aβo. A polymeric degradant of an antibiotic targets Aβo binding sites on PrPC with low nanomolar affinity and prevents Aβo-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrPC affinity in the low to sub-nanomolar range, from both biological (melanin) and synthetic (poly [4-styrenesulfonic acid-co-maleic acid], PSCMA) origin. Association of PSCMA with PrPC prevents Aβo/PrPC-hydrogel formation, blocks Aβo binding to neurons, and abrogates PrPSc production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1ΔE9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrPC-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.

| S-EPMC6358723 | biostudies-literature

Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein.

Project description:Proteolytic processing of the amyloid precursor protein (APP) by beta-secretase, beta-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid beta (Abeta) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP(C)), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, remains enigmatic. Because both APP and PrP(C) are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrP(C) in the proteolytic processing of APP. Cellular overexpression of PrP(C) inhibited the beta-secretase cleavage of APP and reduced Abeta formation. Conversely, depletion of PrP(C) in mouse N2a cells by siRNA led to an increase in Abeta peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, Abeta levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the beta-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP(C) on the beta-secretase cleavage of APP required the localization of PrP(C) to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP(C) via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic Abeta is regulated by PrP(C) and may have implications for both Alzheimer's and prion diseases.

| S-EPMC1904148 | biostudies-literature

Alzheimer's amyloid-? oligomers rescue cellular prion protein induced tau reduction via the Fyn pathway.

Project description:Amyloid-? (A?) and tau are the pathogenic hallmarks in Alzheimer's disease (AD). A? oligomers are considered the actual toxic entities, and the toxicity relies on the presence of tau. Recently, A? oligomers have been shown to specifically interact with cellular prion protein (PrP(C)) where the role of PrP(C) in AD is still not fully understood. To investigate the downstream mechanism of PrP(C) and A? oligomer interaction and their possible relationships to tau, we examined tau expression in human neuroblastoma BE(2)-C cells transfected with murine PrP(C) and studied the effect under A? oligomer treatment. By Western blotting, we found that PrP(C) overexpression down-regulated tau protein and A? oligomer binding alleviated the tau reduction induced by wild type but not M128V PrP(C), the high AD risk polymorphic allele in human prion gene. PrP(C) lacking the A? oligomer binding site was incapable of rescuing the level of tau reduction. Quantitative RT-PCR showed the PrP(C) effect was attributed to tau reduction at the transcription level. Treatment with Fyn pathway inhibitors, Fyn kinase inhibitor PP2 and MEK inhibitor U0126, reversed the PrP(C)-induced tau reduction and A? oligomer treatment modulated Fyn kinase activity. The results suggested Fyn pathway regulated A?-PrP(C)-tau signaling. Overall, our results demonstrated that PrP(C) down-regulated tau via the Fyn pathway and the effect can be regulated by A? oligomers. Our study facilitated the understanding of molecular mechanisms among PrP(C), tau, and A? oligomers.

| S-EPMC3778425 | biostudies-literature

Prion protein modulates cellular iron uptake: a novel function with implications for prion disease pathogenesis.

Project description: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.

| S-EPMC2637434 | biostudies-literature

The role of cellular prion protein in lipid metabolism in the liver.

Project description:Cellular prion protein (PrPC) is a plasma membrane glycophosphatidylinositol-anchored protein and it is involved in multiple functions, including neuroprotection and oxidative stress. So far, most of the PrPC functional research is done in neuronal tissue or cell lines; the role of PrPC in non-neuronal tissues such as liver is only poorly understood. To characterize the role of PrPC in the liver, a proteomics approach was applied in the liver tissue of PrPC knockout mice. The proteome analysis and biochemical validations showed an excessive fat accumulation in the liver of PrPC knockout mice with a change in mRNA expression of genes linked to lipid metabolism. In addition, the higher Bax to Bcl2 ratio, up-regulation of tgfb1 mRNA expression in PrPC knockout mice liver, further showed the evidences of metabolic disease. Over-expression of PrPC in fatty acid-treated AML12 hepatic cell line caused a reduction in excessive intracellular fat accumulation; shows association of PrPC levels and lipid metabolism. Therefore, based on observation of excessive fat globules in the liver of ageing PrPC knockout mice and the reduction of fat accumulation in AML12 cell line with PrPC over-expression, the role of PrPC in lipid metabolism is described.

| S-EPMC7153832 | biostudies-literature

The cellular prion protein traps Alzheimer's A? in an oligomeric form and disassembles amyloid fibers.

Project description:There is now strong evidence to show that the presence of the cellular prion protein (PrP(C)) mediates amyloid-? (A?) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP(C) and A? and discover that substoichiometric amounts of PrP(C), as little as 1/20, relative to A? will strongly inhibit amyloid fibril formation. This effect is specific to the unstructured N-terminal domain of PrP(C). Electron microscopy indicates PrP(C) is able to trap A? in an oligomeric form. Unlike fibers, this oligomeric A? contains antiparallel ? sheet and binds to a oligomer specific conformational antibody. Our NMR studies show that a specific region of PrP(C), notably residues 95-113, binds to A? oligomers, but only once A? misfolds. The ability of PrP(C) to trap and concentrate A? in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrP(C) might confer A? toxicity in AD, as oligomers are thought to be the toxic form of A?. Identification of a specific recognition site on PrP(C) that traps A? in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.

| S-EPMC3767752 | biostudies-literature

Alterations in the brain interactome of the intrinsically disordered N-terminal domain of the cellular prion protein (PrPC) in Alzheimer's disease.

Project description:The cellular prion protein (PrPC) is implicated in neuroprotective signaling and neurotoxic pathways in both prion diseases and Alzheimer's disease (AD). Specifically, the intrinsically disordered N-terminal domain (N-PrP) has been shown to interact with neurotoxic ligands, such as A? and Scrapie prion protein (PrPSc), and to be crucial for the neuroprotective activity of PrPC. To gain further insight into cellular pathways tied to PrP, we analyzed the brain interactome of N-PrP. As a novel approach employing recombinantly expressed PrP and intein-mediated protein ligation, we used N-PrP covalently coupled to beads as a bait for affinity purification. N-PrP beads were incubated with human AD or control brain lysates. N-PrP binding partners were then identified by electrospray ionization tandem mass spectrometry (nano ESI-MS/MS). In addition to newly identified proteins we found many previously described PrP interactors, indicating a crucial role of the intrinsically disordered part of PrP in mediating protein interactions. Moreover, some interactors were found only in either non-AD or AD brain, suggesting aberrant PrPC interactions in the pathogenesis of AD.

| S-EPMC5965872 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data