scholarly journals Expanding spectrum of prion diseases

2020 ◽  
Vol 4 (2) ◽  
pp. 155-167
Author(s):  
Jacob I. Ayers ◽  
Nick A. Paras ◽  
Stanley B. Prusiner
Keyword(s):  
Amino Acids ◽  
Nucleic Acid ◽  
Prion Protein ◽  
Prion Diseases ◽  
Lewy Body Dementia ◽  
Cellular Prion Protein ◽  
Chromosomal Gene ◽  
Scrapie Agent ◽  
Β Sheet ◽  
Translational Process

Prions were initially discovered in studies of scrapie, a transmissible neurodegenerative disease (ND) of sheep and goats thought to be caused by slow viruses. Once scrapie was transmitted to rodents, it was discovered that the scrapie pathogen resisted inactivation by procedures that modify nucleic acids. Eventually, this novel pathogen proved to be a protein of 209 amino acids, which is encoded by a chromosomal gene. After the absence of a nucleic acid within the scrapie agent was established, the mechanism of infectivity posed a conundrum and eliminated a hypothetical virus. Subsequently, the infectious scrapie prion protein (PrPSc) enriched for β-sheet was found to be generated from the cellular prion protein (PrPC) that is predominantly α-helical. The post-translational process that features in nascent prion formation involves a templated conformational change in PrPC that results in an infectious copy of PrPSc. Thus, prions are proteins that adopt alternative conformations, which are self-propagating and found in organisms ranging from yeast to humans. Prions have been found in both Alzheimer's (AD) and Parkinson's (PD) diseases. Mutations in APP and α-synuclein genes have been shown to cause familial AD and PD. Recently, AD was found to be a double prion disorder: both Aβ and tau prions feature in this ND. Increasing evidence argues for α-synuclein prions as the cause of PD, multiple system atrophy, and Lewy body dementia.

scholarly journals Heterogeneity and Architecture of Pathological Prion Protein Assemblies: Time to Revisit the Molecular Basis of the Prion Replication Process?

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 429 ◽  
Author(s):  
Angélique Igel-Egalon ◽  
Jan Bohl ◽  
Mohammed Moudjou ◽  
Laetitia Herzog ◽  
Fabienne Reine ◽  
...  
Keyword(s):  
Prion Protein ◽  
Current Knowledge ◽  
Prion Diseases ◽  
Structural Heterogeneity ◽  
Cellular Prion Protein ◽  
Protein Assemblies ◽  
Replication Process ◽  
Data Points ◽  
Autocatalytic Process ◽  
Β Sheet

Prions are proteinaceous infectious agents responsible for a range of neurodegenerative diseases in animals and humans. Prion particles are assemblies formed from a misfolded, β-sheet rich, aggregation-prone isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Prions replicate by recruiting and converting PrPC into PrPSc, by an autocatalytic process. PrPSc is a pleiomorphic protein as different conformations can dictate different disease phenotypes in the same host species. This is the basis of the strain phenomenon in prion diseases. Recent experimental evidence suggests further structural heterogeneity in PrPSc assemblies within specific prion populations and strains. Still, this diversity is rather seen as a size continuum of assemblies with the same core structure, while analysis of the available experimental data points to the existence of structurally distinct arrangements. The atomic structure of PrPSc has not been elucidated so far, making the prion replication process difficult to understand. All currently available models suggest that PrPSc assemblies exhibit a PrPSc subunit as core constituent, which was recently identified. This review summarizes our current knowledge on prion assembly heterogeneity down to the subunit level and will discuss its importance with regard to the current molecular principles of the prion replication process.

scholarly journals Comparative analysis of heparin affecting the biochemical properties of chicken and murine prion proteins

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247248
Author(s):  
Li-Juan Wang ◽  
Xiao-Dan Gu ◽  
Xiao-Xiao Li ◽  
Liang Shen ◽  
Hong-Fang Ji
Keyword(s):  
Prion Protein ◽  
Conformational Changes ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Mammalian Species ◽  
Biochemical Properties ◽  
Cellular Prion Protein ◽  
Great Loss ◽  
Heparin Concentration ◽  
Β Sheet

The conversion of cellular prion protein (PrPC) to disease-provoking conformer (PrPSc) is crucial in the pathogenesis of prion diseases. Heparin has been shown to enhance mammalian prion protein misfolding. As spontaneous prion disease has not been reported in non-mammalian species, such as chicken, it is interesting to explore the influence of heparin on the conversion of chicken prion protein (ChPrP). Herein, we investigated the influences of heparin on biochemical properties of full-length recombinant ChPrP, with murine prion protein (MoPrP) as control. The results showed that at low heparin concentration (10 μg/mL), a great loss of solubility was observed for both MoPrP and ChPrP using solubility assays. In contrast, when the concentration of heparin was high (30 μg/mL), the solubility of MoPrP and ChPrP both decreased slightly. Using circular dichroism, PK digestion and transmission electron microscopy, significantly increased β-sheet content, PK resistance and size of aggregates were observed for MoPrP interacted with 30 μg/mL heparin, whereas 30 μg/mL heparin-treated ChPrP showed less PK resistance and slight increase of β-sheet structure. Therefore, heparin can induce conformational changes in both MoPrP and ChPrP and the biochemical properties of the aggregates induced by heparin could be modified by heparin concentration. These results highlight the importance of concentration of cofactors affecting PrP misfolding.

Transgenetic investigations of prion diseases of humans and animals

1993 ◽  
Vol 339 (1288) ◽  
pp. 239-254 ◽  
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Prion Diseases ◽  
Gene Mutations ◽  
Single Copy ◽  
Cellular Prion Protein ◽  
Neurological Dysfunction ◽  
New Information ◽  
Prp Gene ◽  
Translational Process

Prions cause transmissible and genetic neurodegenerative diseases. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein (PrP Sc ), which is encoded by a chromosomal gene. Although the PrP gene is single copy, transgenic mice with both alleles of the PrP gene ablated develop normally. A post-translational process, as yet unidentified, converts the cellular prion protein (PrP C ) into PrP Sc . Scrapie incubation times, neuropathology and prion synthesis in transgenic mice are controlled by the PrP gene. Mutations in the PrP gene are genetically linked to development of neurodegeneration. Transgenic mice expressing mutant PrP spontaneously develop neurological dysfunction and spongiform neuropathology. Investigations of prion diseases using transgenesis promise to yield much new information about these once enigmatic disorders.

scholarly journals Pharmacological inactivation of the prion protein by targeting a folding intermediate

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Giovanni Spagnolli ◽  
Tania Massignan ◽  
Andrea Astolfi ◽  
Silvia Biggi ◽  
Marta Rigoli ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Surface Glycoprotein ◽  
Folding Intermediate ◽  
Biological Regulation ◽  
Cell Surface Glycoprotein ◽  
Folding Intermediates ◽  
Protein Levels ◽  
Small Molecule Ligands

AbstractRecent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

scholarly journals Altered toxicity of the prion protein peptide PrP106–126 carrying the Ala117→Val mutation

2000 ◽  
Vol 346 (3) ◽  
pp. 785-791 ◽  
Author(s):  
David R. BROWN
Keyword(s):  
Point Mutation ◽  
Prion Protein ◽  
Prion Diseases ◽  
Point Mutations ◽  
Human Sequence ◽  
Gene Coding ◽  
Normal Human ◽  
Microtubule Formation ◽  
Β Sheet ◽  
Prion Protein Peptide

The inherited prion diseases such as Gerstmann-Sträussler-Scheinker syndrome (GSS) are linked to point mutations in the gene coding for the cellular isoform of the prion protein (PrPC). One particular point mutation A117V (Ala117 → Val) is linked to a variable pathology that usually includes deposition of neurofibrillary tangles. A prion protein peptide carrying this point mutation [PrP106-126(117V)] was generated and compared with a peptide based on the normal human sequence [PrP106-126(117A)]. The inclusion of this point mutation increased the toxicity of PrP106-126 which could be linked to an increased β-sheet content. An assay of microtubule formation in the presence of tau indicated that PrP106-126 decreased the rate of microtubule formation that could be related to the displacement of tau. PrP106-126 carrying the 117 mutation was more efficient at inhibiting microtubule formation. These results suggest a possible mechanism of toxicity for protein carrying this mutation via destabilization of the cytoskeleton and deposition of tau in filaments, as observed in GSS.

scholarly journals The Cellular Prion Protein Prevents Copper-Induced Inhibition of P2X4Receptors

2011 ◽  
Vol 2011 ◽  
pp. 1-6
Author(s):  
Ramón A. Lorca ◽  
Lorena Varela-Nallar ◽  
Nibaldo C. Inestrosa ◽  
J. Pablo Huidobro-Toro
Keyword(s):  
Amino Acids ◽  
Synaptic Transmission ◽  
Prion Protein ◽  
Adenosine Triphosphate ◽  
Response Curve ◽  
Physiological Function ◽  
Cellular Prion Protein ◽  
Synaptic Activity ◽  
Receptor Subtype ◽  
Concentration Response Curve

Although the physiological function of the cellular prion protein (PrPC) remains unknown, several evidences support the notion of its role in copper homeostasis. PrPCbinds Cu2+through a domain composed by four to five repeats of eight amino acids. Previously, we have shown that the perfusion of this domain prevents and reverses the inhibition by Cu2+of the adenosine triphosphate (ATP)-evoked currents in the P2X4receptor subtype, highlighting a modulatory role for PrPCin synaptic transmission through regulation of Cu2+levels. Here, we study the effect of full-length PrPCin Cu2+inhibition of P2X4receptor when both are coexpressed. PrPCexpression does not significantly change the ATP concentration-response curve in oocytes expressing P2X4receptors. However, the presence of PrPCreduces the inhibition by Cu2+of the ATP-elicited currents in these oocytes, confirming our previous observations with the Cu2+binding domain. Thus, our observations suggest a role for PrPCin modulating synaptic activity through binding of extracellular Cu2+.

scholarly journals The Charge Structure of Helix 1 in the Prion Protein Regulates Conversion to Pathogenic PrPSc

2006 ◽  
Vol 80 (17) ◽  
pp. 8521-8529 ◽  
Author(s):  
Eric M. Norstrom ◽  
James A. Mastrianni
Keyword(s):  
Amino Acids ◽  
Prion Protein ◽  
Prion Diseases ◽  
Alpha Helix ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Salt Bridges ◽  
Subsequent Work ◽  
Complete Reversal ◽  
Terminal Amino

ABSTRACT The prion diseases are transmissible neurodegenerative disorders linked to a pathogenic conformer (PrPSc) of the normal prion protein (PrPC). Accumulation of PrPSc occurs via a poorly defined process in which PrPSc complexes with and converts endogenous PrPC to nascent PrPSc. Recent experiments have focused on the highly charged first alpha helix (H1) of PrP. It has been proposed that two putative asparagine-to-arginine intrahelical salt bridges stabilize H1 in PrPC yet form intermolecular ionic bonds with adjacent PrP molecules during conversion of PrPC to PrPSc (M. P. Morrissey and E. I. Shakhnovich, Proc. Natl. Acad. Sci. USA 96:11293-11298, 1999). Subsequent work (J. O. Speare et al., J. Biol. Chem. 278:12522-12529, 2003 using a cell-free assay of PrPSc conversion suggested that rather than promoting conversion, the salt bridges stabilize PrPC against it. However, the role of individual H1 charges in PrPSc generation has not yet been investigated. To approach this question, we systematically reversed or neutralized each charged residue in H1 and tested the effect on conversion to PrPSc in scrapie-infected murine neuroblastoma (ScN2a) cells. We find that replacements of charged H1 residues with like charges permit conversion, while charge reversals hinder it. Neutralization of charges in the N-terminal (amino acids 143 to 146) but not the C-terminal (amino acids 147 to 151) half of H1 permits conversion, while complete reversal of charge orientation of the putative salt bridges produces a nonconvertible PrP. Circular dichroism spectroscopy studies and confocal microscopy immunofluorescence localization studies indicated that charge substitutions did not alter the secondary structure or cell surface expression of PrPC. These data support the necessity of specific charge orientations in H1 for a productive PrPSc-PrPC complex.

scholarly journals The Prion Protein Octarepeat Domain Forms Transient β-sheet Structures Upon Residue-Specific Cu(II) and Zn(II) Binding

2021 ◽  
Author(s):  
Maciej Gielnik ◽  
Aneta Szymanska ◽  
Xiaolin Dong ◽  
Jyri Jarvet ◽  
Zeljko M. Svedruzic ◽  
...  
Keyword(s):  
Metal Ions ◽  
Prion Protein ◽  
Metal Binding ◽  
Cd Spectroscopy ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Amyloid Formation ◽  
Spectroscopy Data ◽  
Spongiform Encephalopathies ◽  
Β Sheet

Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Metal ions appear to play a crucial role in the protein misfolding, and metal imbalance may be part of TSE pathologies. PrPC is a combined Cu(II) and Zn(II) metal binding protein, where the main metal binding site is located in the octarepeat (OR) region. Here, we used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Upon metal binding, the OR region seems to adopt a transient antiparallel β-sheet hairpin structure. Fluorescence spectroscopy data indicates that under neutral conditions, the OR region can bind both Cu(II) and Zn(II) ions, whereas under acidic conditions it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of both metal ions to the OR region results in formation of β-hairpin structures. As formation of β-sheet structures is a first step towards amyloid formation, we propose that high concentrations of either Cu(II) or Zn(II) ions may have a pro-amyloid effect in TSEs.

scholarly journals Prion protein and prion disease at a glance

2021 ◽  
Vol 134 (17) ◽  
Author(s):  
Caihong Zhu ◽  
Adriano Aguzzi
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Future Studies ◽  
Associated Proteins ◽  
Main Component ◽  
Conformational Conversion

ABSTRACT Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main component of prion, PrPSc acts as an infectious template that recruits and converts normal cellular PrPC into its pathogenic, misfolded isoform. Intriguingly, the phenomenon of prionoid, or prion-like, spread has also been observed in many other disease-associated proteins, such as amyloid β (Aβ), tau and α-synuclein. This Cell Science at a Glance and the accompanying poster highlight recently described physiological roles of prion protein and the advanced understanding of pathogenesis of prion disease they have afforded. Importantly, prion protein may also be involved in the pathogenesis of other neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therapeutic studies of prion disease have also exploited novel strategies to combat these devastating diseases. Future studies on prion protein and prion disease will deepen our understanding of the pathogenesis of a broad spectrum of neurodegenerative conditions.

scholarly journals Dimerization of the cellular prion protein inhibits propagation of scrapie prions

2018 ◽  
Vol 293 (21) ◽  
pp. 8020-8031 ◽  
Author(s):  
Anna D. Engelke ◽  
Anika Gonsberg ◽  
Simrika Thapa ◽  
Sebastian Jung ◽  
Sarah Ulbrich ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Conformational Transition ◽  
Prion Diseases ◽  
Neuroblastoma Cells ◽  
Direct Interaction ◽  
Cellular Prion Protein ◽  
Dominant Negative ◽  
Dimerization Domain ◽  
Hydrophobic Domain

A central step in the pathogenesis of prion diseases is the conformational transition of the cellular prion protein (PrPC) into the scrapie isoform, denoted PrPSc. Studies in transgenic mice have indicated that this conversion requires a direct interaction between PrPC and PrPSc; however, insights into the underlying mechanisms are still missing. Interestingly, only a subfraction of PrPC is converted in scrapie-infected cells, suggesting that not all PrPC species are suitable substrates for the conversion. On the basis of the observation that PrPC can form homodimers under physiological conditions with the internal hydrophobic domain (HD) serving as a putative dimerization domain, we wondered whether PrP dimerization is involved in the formation of neurotoxic and/or infectious PrP conformers. Here, we analyzed the possible impact on dimerization of pathogenic mutations in the HD that induce a spontaneous neurodegenerative disease in transgenic mice. Similarly to wildtype (WT) PrPC, the neurotoxic variant PrP(AV3) formed homodimers as well as heterodimers with WTPrPC. Notably, forced PrP dimerization via an intermolecular disulfide bond did not interfere with its maturation and intracellular trafficking. Covalently linked PrP dimers were complex glycosylated, GPI-anchored, and sorted to the outer leaflet of the plasma membrane. However, forced PrPC dimerization completely blocked its conversion into PrPSc in chronically scrapie-infected mouse neuroblastoma cells. Moreover, PrPC dimers had a dominant-negative inhibition effect on the conversion of monomeric PrPC. Our findings suggest that PrPC monomers are the major substrates for PrPSc propagation and that it may be possible to halt prion formation by stabilizing PrPC dimers.

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