Affinage

PRNP

Major prion protein · UniProt P04156

Round 2 corrected
Length
253 aa
Mass
27.7 kDa
Annotated
2026-04-28
130 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRNP encodes the cellular prion protein (PrPC), a GPI-anchored glycoprotein whose structured C-terminal domain contains three α-helices and an antiparallel β-sheet, while its disordered N-terminal tail harbors octapeptide repeats that coordinate Cu²⁺ via His-Gly-Gly equatorial ligation (PMID:10618385, PMID:11900542). PrPC resides in cholesterol-rich caveolae-like membrane rafts where it signals through caveolin-1–coupled Fyn kinase in differentiated neurons, serves as a high-affinity receptor for amyloid-β oligomers—activating Fyn/NR2B phosphorylation and mGluR5-dependent synaptic dysfunction—and engages STI1 to trigger neuroprotective SOD upregulation and anti-apoptotic signaling (PMID:10988071, PMID:19242475, PMID:22820466, PMID:24012003, PMID:12093732, PMID:15670743). Pathogenic conversion to protease-resistant PrPSc requires GPI-anchor-directed raft localization and is modulated by codon 129 homozygosity, N-glycosylation at residues 181/197, and normal α-cleavage by ADAM proteases near residue 109 that disrupts the amyloidogenic region; misfolded PrP retrotranslocated to the cytosol is independently neurotoxic (PMID:27847358, PMID:1677164, PMID:29989689, PMID:24721836, PMID:12386337, PMID:8962161). Missense mutations (P102L, D178N) and octapeptide repeat expansions in PRNP cause inherited prion diseases including Gerstmann-Sträussler syndrome, fatal familial insomnia, and familial CJD, with the codon 129 polymorphism on the mutant allele determining the clinical phenotype (PMID:2564168, PMID:1346338, PMID:1439789, PMID:1683708).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1986 High

    Cloning human PRNP cDNA established the primary structure of PrP—including signal peptide, N-glycosylation sites, and high conservation with hamster PrP—providing the molecular framework for all subsequent functional studies.

    Evidence cDNA library screening and DNA sequencing of human PrP

    PMID:3755672

    Open questions at the time
    • No three-dimensional structure yet available
    • Function of glycosylation sites unknown
    • GPI anchoring not yet characterized
  2. 1989 High

    Identification of the P102L mutation in Gerstmann-Sträussler syndrome families established that single missense mutations in PRNP cause inherited prion disease, proving the gene is directly pathogenic and not merely a host factor.

    Evidence Genetic linkage analysis and DNA sequencing in two independent GSS pedigrees

    PMID:2564168

    Open questions at the time
    • Mechanism by which P102L promotes misfolding unknown
    • Relationship between genetic and sporadic prion disease unclear
  3. 1991 High

    Two key discoveries—that codon 129 homozygosity predisposes to sporadic CJD and that octapeptide repeat expansions cause familial CJD—revealed that both coding polymorphisms and repeat-length variants govern prion disease susceptibility, implicating intermolecular PrP-PrP interactions in propagation.

    Evidence Case-control genotyping (codon 129) and PRNP sequencing with neuropathological/transmission validation (repeat expansions)

    PMID:1677164 PMID:1683708

    Open questions at the time
    • Structural basis of codon 129 effect on conversion unknown
    • Minimum repeat expansion required for disease not defined
  4. 1992 High

    Linking the D178N mutation to both fatal familial insomnia and familial CJD—with the phenotype determined by cis codon 129 Met versus Val—demonstrated that a single mutation can produce distinct prion diseases through allele-specific conformational modulation of PrP.

    Evidence PRNP sequencing, proteinase K Western blot, and segregation analysis across 11 kindreds

    PMID:1346338 PMID:1439789

    Open questions at the time
    • Structural difference between FFI-PrPSc and fCJD-PrPSc unknown
    • How codon 129 alters PrP folding trajectory not resolved
  5. 1995 High

    Identification of normal α-cleavage at His-111/Met-112 generating the C1 fragment, and reconstitution of PrPSc-like conversion in vitro using α-helical PrP peptides, together defined both the physiological processing that limits PrP toxicity and the minimal molecular interaction (α-helical domains) sufficient for pathogenic misfolding.

    Evidence N-terminal sequencing of purified C1 from brain; in vitro peptide-PrPC mixing with ultracentrifugation, CD, and protease resistance readouts

    PMID:7479957 PMID:7642585

    Open questions at the time
    • Identity of the protease(s) performing α-cleavage in vivo not yet determined
    • Whether α-cleavage actively protects against prion propagation in vivo untested
  6. 1996 High

    Demonstrating that PrPC and PrPSc co-localize in caveolae-like raft domains—and that the N-terminal 49 residues are dispensable for scrapie susceptibility—established that raft microdomains are the conversion site and that PrP's C-terminal structured domain is sufficient for prion propagation.

    Evidence Detergent-resistant membrane fractionation in two species; transgenic PrP-null mouse rescue with N-terminally truncated PrP constructs

    PMID:8635458 PMID:8962161

    Open questions at the time
    • Whether raft disruption prevents conversion in vivo not tested
    • Role of specific raft lipid species unknown
  7. 2000 High

    The NMR solution structure of full-length human PrP and the discovery of caveolin-1/Fyn kinase signaling transformed understanding of PrPC from a passive substrate for conversion to a structured signaling protein whose globular domain interacts with its disordered N-terminal tail.

    Evidence NMR spectroscopy of recombinant PrP(23-230); antibody cross-linking Fyn activation assay in differentiated 1C11 neuronal cells

    PMID:10618385 PMID:10988071

    Open questions at the time
    • Endogenous PrPC ligands that trigger Fyn signaling unknown
    • Whether N-terminal tail modulates signaling not tested
  8. 2002 High

    Three advances—atomic-resolution Cu²⁺ coordination in octapeptide repeats, identification of STI1 as a neuroprotective PrPC ligand, and demonstration that cytosolic PrP is acutely neurotoxic—revealed PrPC as a copper-binding signaling receptor with a misfolding-independent neurotoxic pathway when mislocalized to the cytosol.

    Evidence X-ray crystallography and EPR of HGGGW-Cu²⁺; GST pull-down and co-IP of PrPC-STI1 with apoptosis rescue; transgenic mice expressing cytosolic PrP with cerebellar degeneration

    PMID:11900542 PMID:12093732 PMID:12386337

    Open questions at the time
    • Whether Cu²⁺ binding is physiologically required for PrPC function in vivo unclear
    • Mechanism of cytosolic PrP toxicity at the molecular level unknown
  9. 2003 High

    Anti-PrP antibody therapy dramatically prolonged survival in scrapie-infected mice by blocking cell-surface PrPC availability, directly proving that surface PrPC is the rate-limiting substrate for prion propagation and validating immunotherapy as a therapeutic strategy.

    Evidence Passive anti-PrP monoclonal antibody transfer in murine scrapie model with survival, PrPSc, and infectivity bioassays

    PMID:12621436

    Open questions at the time
    • CNS penetration of antibodies not achieved
    • Whether antibodies work post-clinical onset unknown
  10. 2009 High

    The discovery that PrPC is a high-affinity receptor for Aβ oligomers—mediating LTP blockade that is absent in PrP-null mice—unexpectedly connected PrPC to Alzheimer's disease synaptotoxicity, expanding its pathological relevance beyond prion diseases.

    Evidence Expression cloning screen, surface plasmon resonance, hippocampal slice electrophysiology in wild-type and PrP-KO mice, anti-PrP antibody rescue

    PMID:19242475

    Open questions at the time
    • Binding site on PrPC for Aβo not precisely mapped
    • Whether PrPC-Aβo interaction occurs in human AD brain not directly shown
  11. 2012 High

    Elucidation of the downstream Aβo→PrPC→Fyn→NR2B phosphorylation cascade—causing NMDAR dysregulation, spine loss, and neuronal death—provided a complete signaling pathway linking PrPC to Alzheimer-type synaptic destruction.

    Evidence Co-IP, Fyn kinase assays, NMDAR surface biotinylation, spine imaging, PrP-null and Fyn-null mouse genetics

    PMID:22820466

    Open questions at the time
    • Therapeutic efficacy of Fyn inhibition in AD models not tested in this study
    • Contribution of this pathway relative to PrPC-independent Aβo toxicity unclear
  12. 2013 High

    Identification of mGluR5 as the transmembrane co-receptor coupling extracellular PrPC-Aβo complexes to intracellular Fyn and Ca²⁺ signaling completed the receptor architecture and demonstrated pharmacological reversibility of cognitive deficits via mGluR5 antagonism.

    Evidence Reconstitution in Xenopus oocytes, co-IP of PrPC-mGluR5, Ca²⁺ imaging, behavioral rescue with mGluR5 antagonist in AD transgenic mice

    PMID:24012003

    Open questions at the time
    • Structural basis of PrPC-mGluR5 interaction unknown
    • Whether mGluR5 antagonism is effective in human AD untested
  13. 2013 Medium

    Demonstrating that autophagy delivers misfolded PrP from the ER to lysosomes—and that autophagy inhibition increases protease-resistant PrP—identified autophagy as a cellular quality-control mechanism limiting PrPSc accumulation.

    Evidence Live-cell imaging of GFP-mutant PrP, ATG5-KO MEFs, 3-MA and rapamycin treatments with protease resistance readouts

    PMID:24454378

    Open questions at the time
    • Whether autophagy induction clears PrPSc in vivo during active prion infection not tested
    • Receptor(s) mediating selective PrP autophagy not identified
  14. 2014 Medium

    Mapping three distinct ADAM protease α-cleavage sites near residue 109 and showing that the minimal lethal PrP deletion encompasses all three sites established α-cleavage as essential for limiting PrPC-intrinsic toxicity, with copper and zinc modulating cleavage efficiency.

    Evidence In vitro ADAM8/10/17 cleavage assays with recombinant PrP, metal modulation, correlation with published deletion mutant lethality data

    PMID:24721836

    Open questions at the time
    • Which ADAM protease is rate-limiting for α-cleavage in neurons not determined
    • In vivo validation of copper/zinc modulation lacking
  15. 2017 High

    Three convergent findings—that GPI-anchored raft association is required for persistent PrPSc propagation, that the native α-helical state kinetically inhibits amyloid formation, and that N-glycans at positions 181/197 sterically block aggregation—defined the biophysical constraints governing the conversion threshold.

    Evidence GPI vs. transmembrane PrP in prion-infected null cells; ThT kinetic assays with enzyme-kinetic modeling; semisynthetic PEG-glycan PrP aggregation assays

    PMID:27847358 PMID:28373719 PMID:28989689

    Open questions at the time
    • Whether glycosylation-site occupancy varies in disease-affected brain regions unknown
    • Kinetic model not validated with authentic brain-derived PrPSc seeds
  16. 2020 High

    Complete prion resistance in PRNP-null goats after intracerebral inoculation—with dose-dependent delay in heterozygotes—provided definitive in vivo proof that PrPC expression level is the rate-limiting determinant of prion disease.

    Evidence Intracerebral scrapie inoculation of naturally occurring PRNP-null, heterozygous, and wild-type goats with IHC, EIA, and RT-QuIC

    PMID:31924264

    Open questions at the time
    • Whether PrPC ablation produces any long-term neurological deficits in goats not reported
    • Applicability to human PRNP reduction strategies not tested
  17. 2024 Medium

    The finding that creatine directly binds PrP and inhibits its Fe³⁺→Fe²⁺ reductase activity to confer ferroptosis resistance in endometriotic cells revealed an unanticipated iron-regulatory function for PrP outside the nervous system.

    Evidence DARTS target identification, cellular iron uptake assays, ferroptosis viability assays in patient-derived endometrial stromal cells

    PMID:39119937

    Open questions at the time
    • Structural basis of creatine-PrP binding unknown
    • Whether PrP's iron reductase activity is relevant in neurons not established
    • Single study requiring independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of infectious PrPSc, the identity of endogenous ligands that activate PrPC-Fyn signaling under physiological conditions, and whether therapeutic reduction of PrPC expression (e.g., ASO) can be tolerated long-term without compromising PrPC's neuroprotective and copper-trafficking functions.
  • No atomic-resolution PrPSc structure available
  • Physiological PrPC activating ligand unknown
  • Long-term safety of PrPC depletion in humans untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 6 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 8 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-9612973 Autophagy 2
Partners
ADAM10ADAM17CAV1FYNGRIN2BGRM5STIP1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 NMR solution structure of human PrP(23-230) revealed a globular C-terminal domain (residues 125-228) containing three α-helices (144-154, 173-194, 200-228) and a short antiparallel β-sheet (128-131, 161-164), with an N-terminal flexibly disordered tail; local conformational states of helices 2 and 3 are influenced by N-terminal tail length. NMR spectroscopy (solution structure of recombinant full-length and truncated human PrP) Proceedings of the National Academy of Sciences of the United States of America High 10618385
1989 A missense mutation at PRNP codon 102 (Pro→Leu) is linked to Gerstmann-Sträussler syndrome, establishing that a pathogenic mutation in the prion protein gene causes inherited prion disease. Genetic linkage analysis in GSS pedigrees; DNA sequencing of PRNP Nature High 2564168
1991 Homozygosity at PRNP codon 129 (Met/Met or Val/Val) strongly predisposes to sporadic Creutzfeldt-Jakob disease, indicating that heterozygosity at this polymorphic site is protective, consistent with a mechanism requiring intermolecular PrP-PrP interaction during prion propagation. Case-control genotyping of codon 129 in sporadic CJD patients versus normal controls Nature High 1677164
1992 Fatal familial insomnia and a subtype of familial CJD are both linked to the same Asn178 mutation in PRNP, but the distinct disease phenotypes are determined by the codon 129 Met/Val polymorphism on the mutant allele: Met129-Asn178 segregates with FFI, Val129-Asn178 with familial CJD. Segregation analysis and PRNP sequencing/restriction analysis in multiple kindreds Science High 1439789
1992 Fatal familial insomnia is caused by a point mutation at PRNP codon 178 (Asp→Asn), producing a protease-resistant PrP isoform with a distinct fragment pattern from that of CJD, demonstrating that codon 178 mutation alters PrP conformation and disease phenotype. PRNP sequencing, proteinase K digestion + Western blot, restriction enzyme analysis, linkage analysis The New England Journal of Medicine High 1346338
1991 Insertions of 5, 7, or 8 extra octapeptide coding repeats in the PRNP gene (resulting in 10–13 total repeats) are associated with familial transmissible CJD, establishing that expansion of the octapeptide repeat region of PrP causes inherited prion disease. PRNP sequencing and family screening of confirmed neuropathologically and experimentally transmitted CJD cases Proceedings of the National Academy of Sciences of the United States of America High 1683708
1996 Both PrPC and PrPSc co-localize in caveolae-like detergent-insoluble membrane domains (CLDs/rafts) isolated from scrapie-infected neuroblastoma cells and Syrian hamster brain, supporting the hypothesis that PrPSc formation occurs within these cholesterol-rich membrane microdomains. Subcellular fractionation (Triton X-100 and detergent-free sonication), sucrose gradient flotation, sulfo-NHS-biotin cell-surface labeling, Western blot Proceedings of the National Academy of Sciences of the United States of America High 8962161
1996 PrP transgenes lacking the N-terminal 26 or 49 amino-proximal residues fully restore susceptibility to scrapie, prion propagation, and PrPSc accumulation in PrP-knockout mice, demonstrating that the amino-proximal domain of PrPC is dispensable for conversion to PrPSc. Transgenic mouse inoculation with scrapie prions; Western blot for PrPSc accumulation; disease bioassay The EMBO journal High 8635458
2000 PrPC mediates signal transduction through a caveolin-1-dependent coupling to the tyrosine kinase Fyn upon antibody-mediated cross-linking; this signaling is restricted to fully differentiated serotonergic and noradrenergic neuronal cells and occurs primarily at neurites. Antibody cross-linking in neuronal differentiation cell model (1C11), Western blot for Fyn phosphorylation, caveolin-1 dependence assessed by overexpression/disruption Science High 10988071
2002 Crystal structure of the octapeptide HGGGW–Cu2+ complex reveals equatorial coordination of Cu2+ by the histidine imidazole, two deprotonated glycine amides, and a glycine carbonyl, with axial water bridging to the Trp indole; EPR and ESEEM confirm this structure is maintained in the full PrP octarepeat domain in solution and that the Gly-Cu linkage is unstable below pH ~6.5, suggesting a pH-dependent mechanism for Cu2+ release in endosomes. X-ray crystallography, S-band EPR, X-band ESEEM, HYSCORE spectroscopy on 15N-labeled peptides and full PrP octarepeat domain Biochemistry High 11900542
2002 Stress-inducible protein 1 (STI1) is a cell-surface ligand for PrPC; the interaction is high-affinity (Kd ~10-7 M), mapped to PrPC residues 113-128 and STI1 residues 230-245, confirmed by co-immunoprecipitation in vivo, and triggers neuroprotective signals that rescue cells from apoptosis. Cell-surface binding assays, GST pull-down, co-immunoprecipitation, peptide competition, neuroprotection assays (apoptosis rescue) The EMBO journal High 12093732
2002 Accumulation of cytosolic PrP (misfolded PrP retrotranslocated from the ER to the cytosol) is strongly neurotoxic in cultured cells and transgenic mice, producing fatal cerebellar ataxia with cerebellar degeneration and gliosis, establishing a mechanism for wild-type PrP to acquire neurotoxicity distinct from PrPSc. Transgenic mouse model expressing cytosolic PrP; immunofluorescence; histopathology (cerebellar degeneration, gliosis); cell toxicity assays Science High 12386337
1995 PrPC is proteolytically cleaved in normal brain to generate a major C-terminal fragment (C1) with N-termini at His-111 or Met-112; C1 is glycosylated and GPI-anchored like PrPC, and this cleavage disrupts the neurotoxic/amyloidogenic region 106-126, suggesting C1 generation as a normal metabolic event that may limit pathogenicity. N-terminal sequencing of purified C1 fragment, Western blot, biochemical characterization (glycosylation, GPI-anchor, detergent solubility, protease resistance) The Journal of Biological Chemistry High 7642585
1986 Molecular cloning of the human PrP cDNA revealed an open reading frame encoding a protein with an N-terminal signal peptide, two hydrophobic membrane-spanning segments, and two N-glycosylation sites; human PrP shares ~90% amino acid identity with hamster PrP. cDNA library screening, DNA sequencing, Northern blot analysis DNA (Mary Ann Liebert, Inc.) High 3755672
2009 Cellular PrPC is a high-affinity cell-surface receptor for soluble amyloid-beta oligomers (Aβo); Aβo binding to PrPC mediates blockade of hippocampal long-term potentiation, and PrP-null mice are resistant to Aβo-induced LTP inhibition; anti-PrP antibodies rescue synaptic plasticity. Expression cloning screen, surface plasmon resonance (Kd measurement), hippocampal slice electrophysiology (LTP), PrP knockout mice, anti-PrP antibody rescue Nature High 19242475
2012 Aβ oligomers bound to postsynaptic PrPC activate Fyn kinase, leading to NR2B subunit phosphorylation of NMDARs, initial increase then loss of surface NMDARs, dendritic spine loss, and neuronal death; both PrPC and Fyn are required for Aβo-induced spine loss and Alzheimer transgene-driven seizures in mice. Co-immunoprecipitation, Fyn kinase assays, NMDAR surface expression by biotinylation, dendritic spine imaging, LDH cytotoxicity, PrP-null and Fyn-null mouse genetics, human AD brain extract assays Nature Neuroscience High 22820466
2013 Metabotropic glutamate receptor 5 (mGluR5) acts as a transmembrane co-receptor for the Aβo-PrPC complex at the postsynaptic density; PrPC and mGluR5 physically interact, mGluR5 couples PrPC-bound Aβo to intracellular Fyn and to elevated intracellular Ca2+, eEF2 phosphorylation, and dendritic spine loss; mGluR5 antagonism reverses learning/memory deficits and synapse loss in familial AD transgenic mice. Heterologous co-expression screen (Xenopus oocytes), co-immunoprecipitation (PrPC-mGluR5 interaction), Ca2+ imaging, Fyn kinase assays, dendritic spine counting, behavioral testing in AD transgenic mice, mGluR5 antagonist treatment Neuron High 24012003
2003 Monoclonal anti-PrP antibodies markedly reduce peripheral PrPSc levels and prion infectivity in a murine scrapie model when administered peripherally, and prolong survival >300 days beyond untreated controls, demonstrating that PrPC on the cell surface is a required substrate for prion propagation that can be blocked by antibody. In vivo murine scrapie model: passive antibody transfer, Western blot for PrPSc, bioassay for prion infectivity, survival analysis Nature High 12621436
1995 Synthetic PrP peptides encompassing the two alpha-helical domains of PrP, when in random-coil (not beta-sheet) conformation, form a complex with PrPC that induces many PrPSc-like properties: fibrous aggregation, sedimentation at 100,000×g, protease resistance, and high beta-sheet content; the pathogenic A117V mutation enhances complex formation, and anti-PrP antibody prevents it. In vitro mixing of synthetic peptides with PrPC, ultracentrifugation, circular dichroism, protease resistance assay, electron microscopy, antibody inhibition Proceedings of the National Academy of Sciences of the United States of America High 7479957
2003 Cell-surface PrPC constitutively cycles between the plasma membrane and early endosomes via a clathrin-dependent mechanism; this pathway is consistent with a role for PrPC in cellular copper ion trafficking; mutations linked to inherited prion diseases display abnormalities in maturation and localization. Cell biological trafficking studies: internalization assays, endosome colocalization, clathrin-dependence experiments (review summarizing experimental findings) British Medical Bulletin Medium 14522850
2005 PrPC cooperates with STI1 to upregulate SOD (superoxide dismutase) activity in neuronal cells; PrPC co-immunoprecipitates with STI1; inhibitory peptides against PrPC-STI1 binding (STI1 pep.1 and PrP(113-132)) reduce SOD activity and induce toxicity in PrPC-expressing but not in Prnp−/− cells; the octapeptide repeat region and N-terminal half of the hydrophobic region of PrPC are required for this effect. Co-immunoprecipitation (PrPC-STI1), inhibitory peptide treatments, SOD activity assay, apoptosis assay in Prnp−/− and wild-type neuronal cell lines Biochemical and Biophysical Research Communications Medium 15670743
2004 Anti-PrP monoclonal antibodies prevent PrPSc accumulation by retaining PrPC on the cell surface rather than allowing its internalization; mAbs binding the cell surface (regardless of epitope: C-terminal core or N-terminal octapeptide region) block PrPSc formation at ~1 nM EC50; forced internalization with dextran sulfate overcomes antibody protection. Flow cytometry (PrPC surface retention), prion-infected cell culture (PrPSc accumulation by Western blot), dextran sulfate internalization assay The Journal of General Virology Medium 15483265
2010 The conserved middle region of PrP (positively charged segment + hydrophobic domain) is essential for lipid-induced PrP conversion: the hydrophobic domain mediates hydrophobic PrP-lipid interaction required for C-terminal protease resistance, while the positively charged region contributes to electrostatic lipid binding; disease-associated P102L/P105L mutations and the codon 129 polymorphism alter lipid-induced PrP conversion. In vitro proteinase K resistance assays of recombinant PrP mutants incubated with anionic lipids, lipid-binding assays, site-directed mutagenesis Biochemistry Medium 20718504
2014 PrPC undergoes α-cleavage near residue 109 by ADAM proteases (ADAM8, 10, 17) at three distinct sites; copper and zinc modulate proteolytic efficiency; the minimal lethal deletion segment in PrPC fully encompasses all three α-cleavage sites, suggesting that α-cleavage is essential for downregulating PrPC activity and that its blockade with retention of N-terminal residues 23-31 confers a toxic phenotype. In vitro ADAM protease cleavage assays with recombinant PrP, biophysical characterization of cleavage sites, analysis of published PrP deletion mutant phenotypes Prion Medium 24721836
2017 GPI anchor-directed membrane association of PrPC is required for persistent PrPres propagation in cell culture; transmembrane PrPC variants (redirected away from lipid rafts) resist conversion by multiple prion strains and by both raft-associated and purified GPI-anchorless amyloid fibrils, implicating raft microdomains as the site of PrPC-to-PrPres conversion. PrP-knockout neuronal cell line (NpL2) transfected with GPI-anchored vs. transmembrane-anchored PrPC; infection with multiple prion strains; PrPres detection by Western blot Journal of Virology High 27847358
2013 Autophagy delivers disease-associated misfolded PrP (T182A mutant) from the ER to lysosomes in a Golgi-independent manner; autophagy inhibition (ATG5 knockout or 3-MA) reduces PrP-lysosome colocalization and increases insoluble, protease-resistant PrP, while autophagy induction (rapamycin) reduces it, demonstrating autophagy functions as a quality-control mechanism limiting PrPSc accumulation. Time-lapse live-cell imaging (GFP-Mut-PrP + LysoTracker), ATG5−/− mouse embryonic fibroblasts, 3-MA and rapamycin treatments, protease resistance assays, LC3B colocalization International Journal of Cell Biology Medium 24454378
2013 PrP peptide 106-126 (PrP106-126) induces temporal mitophagy in neuronal cells (N2a) that requires cardiolipin (CL) externalization to the mitochondrial surface; knockdown of CL synthase or CL translocation proteins (phospholipid scramblase-3, NDPK-D) reduces PrP106-126-induced mitophagy and decreases PINK1/DRP1 recruitment, while impairing CL redistribution leads to mitochondrial dysfunction. CL synthase/PLSCR3/NDPK-D siRNA knockdown, mitophagy assays, PINK1/Parkin/DRP1 recruitment by immunofluorescence, oxidative phosphorylation measurement, ROS detection in N2a cells Frontiers in Molecular Neuroscience Medium 37333615
2024 Creatine binds directly to PrP (identified by DARTS assay), inhibits PrP-mediated conversion of Fe3+ to Fe2+, and thereby decreases intracellular iron uptake, promoting ferroptosis resistance in ectopic endometrial stromal cells; creatine accumulation in endometriosis lesions thus exploits PrP's iron-regulatory activity to enhance cell survival. DARTS (drug affinity responsive target stabilization) assay, cellular iron assays, ferroptosis viability assays, creatine supplementation experiments in patient-derived cells Advanced Science Medium 39119937
2017 The native α-helical state of PrP acts as an uncompetitive or noncompetitive inhibitor of PrP amyloid fibril formation in vitro; quantitative kinetic analysis shows that destabilization of the native state promotes amyloid formation by relieving this inhibition. Thioflavin T fluorescence kinetic assays, varying concentrations of pre-formed amyloid seeds, monomer, and denaturant; enzyme kinetic modeling Scientific Reports Medium 28373719
2017 Semisynthetic PrP variants carrying PEG-based N-glycan mimics at glycosylation sites 181 and 197 do not form amyloid fibrils under conditions that cause wild-type PrP to aggregate; addition of as little as 10 mol% PEGylated PrP to wild-type PrP completely blocks aggregation, suggesting N-glycans sterically inhibit PrP aggregation in vivo. Semisynthetic protein chemistry, in vitro aggregation assays, CD spectroscopy, ThT fluorescence Chemical Science Medium 28989689
2020 Goats homozygous for a naturally occurring nonsense mutation (Ter) in PRNP that blocks PrPC synthesis are completely resistant to scrapie after intracerebral inoculation (no clinical signs, no PrPSc, no vacuolation at 1260 days post-inoculation), while wild-type goats succumb at ~601 days; heterozygotes show delayed disease (~773 days), demonstrating that PrPC expression level is a prerequisite and rate-limiting factor for prion disease. Intracerebral prion inoculation of PRNP+/+, PRNP+/Ter, and PRNPTer/Ter goats; immunohistochemistry, enzyme immunoassay, RT-QuIC for PrPSc Veterinary Research High 31924264
2013 The ZIP5 zinc transporter ectodomain (a PrP-like domain from an LZT family member) co-localizes with PrPC at the cell surface and shares the same Rab5-positive endocytic vesicles, and adopts a dimeric α-helical fold similar to PrPC, supporting the evolutionary origin of the prion protein family from ancestral LZT zinc transporter genes. Confocal microscopy colocalization (ZIP5 and PrPC in neuroblastoma cells), Rab5 endocytic marker colocalization, recombinant expression and biophysical characterization (CD, SEC) of ZIP5 PrP-like domain PLoS ONE Medium 24039764

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2016 The Cellular Phase of Alzheimer's Disease. Cell 1446 26871627
2007 Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature genetics 1399 17192785
2009 Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 1272 19242475
2001 Prion diseases of humans and animals: their causes and molecular basis. Annual review of neuroscience 1018 11283320
1993 Thiamine-repressible expression vectors pREP and pRIP for fission yeast. Gene 970 8422996
2000 NMR solution structure of the human prion protein. Proceedings of the National Academy of Sciences of the United States of America 878 10618385
2014 Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 790 24857020
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1996 Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. The EMBO journal 746 8635458
1989 Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature 728 2564168
1991 Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 713 1677164
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2000 Signal transduction through prion protein. Science (New York, N.Y.) 626 10988071
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
1992 Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science (New York, N.Y.) 568 1439789
2012 Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature neuroscience 543 22820466
2013 Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 480 24012003
1992 Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. The New England journal of medicine 480 1346338
1996 Subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains. Proceedings of the National Academy of Sciences of the United States of America 451 8962161
1995 Truncated forms of the human prion protein in normal brain and in prion diseases. The Journal of biological chemistry 450 7642585
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2003 Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 383 12621436
2002 Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science (New York, N.Y.) 383 12386337
2002 Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. The EMBO journal 336 12093732
2007 Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS genetics 325 17500595
2005 Genetic prion disease: the EUROCJD experience. Human genetics 322 16187142
2002 Molecular features of the copper binding sites in the octarepeat domain of the prion protein. Biochemistry 315 11900542
1986 Molecular cloning of a human prion protein cDNA. DNA (Mary Ann Liebert, Inc.) 311 3755672
1991 Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proceedings of the National Academy of Sciences of the United States of America 297 1683708
1997 RNA aptamers specifically interact with the prion protein PrP. Journal of virology 175 9343239
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