scholarly journals Vaccination with Prion Peptide-Displaying Polyomavirus-Like Particles Prolongs Incubation Time in Scrapie-Infected Mice

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 811
Author(s):  
Martin Eiden ◽  
Alma Gedvilaite ◽  
Fabienne Leidel ◽  
Rainer G. Ulrich ◽  
Martin H. Groschup
Keyword(s):  
Prion Diseases ◽  
Mammalian Species ◽  
Cellular Prion Protein ◽  
Control Group ◽  
Spongiform Encephalopathy ◽  
Post Inoculation ◽  
Self Tolerance ◽  
Jakob Disease ◽  
Capsid Protein Vp1 ◽  
Conformational Conversion

Prion diseases like scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle or Creutzfeldt–Jakob disease (CJD) in humans are fatal neurodegenerative diseases characterized by the conformational conversion of the normal, mainly α-helical cellular prion protein (PrPC) into the abnormal β-sheet rich infectious isoform PrPSc. Various therapeutic or prophylactic approaches have been conducted, but no approved therapeutic treatment is available so far. Immunisation against prions is hampered by the self-tolerance to PrPC in mammalian species. One strategy to avoid this tolerance is presenting PrP variants in virus-like particles (VLPs). Therefore, we vaccinated C57/BL6 mice with nine prion peptide variants presented by hamster polyomavirus capsid protein VP1/VP2-derived VLPs. Mice were subsequently challenged intraperitoneally with the murine RML prion strain. Importantly, one group exhibited significantly increased mean survival time of 240 days post-inoculation compared with 202 days of the control group. These data show that immunisation with VLPs presenting PrP peptides may represent a promising strategy for an effective vaccination against transmissible spongiform encephalitis agents.

scholarly journals Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Hideyuki Hara ◽  
Hironori Miyata ◽  
Nandita Rani Das ◽  
Junji Chida ◽  
Tatenobu Yoshimochi ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Prion Diseases ◽  
Spongiform Encephalopathy ◽  
Wild Type ◽  
Jakob Disease ◽  
Function Relationship ◽  
Different Strains ◽  
Conformational Conversion

ABSTRACTConformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrPCinto PrPScafter infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/Prnp0/0mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPScΔOR in their brains. We show here that Tg(PrPΔOR)/Prnp0/0mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrPScΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrPCinto PrPScafter infection with BSE prions. However, Tg(PrPΔOR)/Prnp0/0mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPScΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/Prnp0/0mice than PrPScin control wild-type mice. Taken together, these results indicate that the OR region of PrPCcould play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions.IMPORTANCEStructure-function relationship studies of PrPCconformational conversion into PrPScare worthwhile to understand the mechanism of the conversion of PrPCinto PrPSc. We show here that, by inoculating Tg(PrPΔOR)/Prnp0/0mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrPCinto PrPScafter infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPScΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPScΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrPCinto PrPScafter infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.

Biology of the prion gene complex

2001 ◽  
Vol 79 (5) ◽  
pp. 613-628 ◽  
Author(s):  
Peter Mastrangelo ◽  
David Westaway
Keyword(s):  
Prion Protein ◽  
Protein Function ◽  
Prion Diseases ◽  
Mammalian Species ◽  
Prnp Gene ◽  
Spongiform Encephalopathy ◽  
Missense Mutations ◽  
Point Of Entry ◽  
Major Structural Component ◽  
Jakob Disease

The prion protein gene Prnp encodes PrPSc, the major structural component of prions, infectious pathogens causing a number of disorders including scrapie and bovine spongiform encephalopathy (BSE). Missense mutations in the human Prnp gene, PRNP, cause inherited prion diseases such as familial Creutzfeldt–Jakob Disease. In uninfected animals, Prnp encodes a GPI-anchored protein denoted PrPC, and in prion infections, PrPCis converted to PrPScby templated refolding. Although Prnp is conserved in mammalian species, attempts to verify interactions of putative PrP-binding proteins by genetic means have proven frustrating in that two independent lines of Prnp gene ablated mice (Prnp0/0mice: ZrchI and Npu) lacking PrPCremain healthy throughout development. This indicates that PrPCserves a function that is not apparent in a laboratory setting or that other molecules have overlapping functions. Shuttling or sequestration of synaptic Cu(II) via binding to N-terminal octapeptide residues and (or) signal transduction involving the fyn kinase are possibilities currently under consideration. A new point of entry into the issue of prion protein function has emerged from identification of a paralog, Prnd, with 25% coding sequence identity to Prnp. Prnd lies downstream of Prnp and encodes the Dpl protein. Like PrPC, Dpl is presented on the cell surface via a GPI anchor and has three α-helices: however, it lacks the conformationally plastic and octapeptide repeat domains present in its well-known relative. Interestingly, Dpl is overexpressed in two other lines of Prnp0/0mice (Ngsk and Rcm0) via intergenic splicing events. These lines of Prnp0/0mice exhibit ataxia and apoptosis of cerebellar cells, indicating that ectopic synthesis of Dpl protein is toxic to CNS neurons: this inference has now been confirmed by the construction of transgenic mice expressing Dpl under the direct control of the PrP promoter. Remarkably, Dpl-programmed ataxia is rescued by wt Prnp transgenes. The interaction between the Prnp and Prnd genes in mouse cerebellar neurons may have a physical correlate in competition between Dpl and PrPCwithin a common biochemical pathway that, when misregulated, leads to apoptosis.Key words: spongiform encephalopathy, neurodegenerative disease, paralogs, scrapie, CJD.

scholarly journals From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Isabelle Acquatella-Tran Van Ba ◽  
Thibaut Imberdis ◽  
Véronique Perrier
Keyword(s):  
Neurodegenerative Disorders ◽  
Small Rnas ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Original Works ◽  
Jakob Disease ◽  
The Brain ◽  
Prion Hypothesis

Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrPSc, an abnormalβ-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSccan trigger the autocatalytic conversion of PrPCinto PrPSc, presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of “deformed templating” regarding a new mechanism of PrPScformation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease and tauopathies.

Human prion diseases

2020 ◽  
pp. 6109-6119
Author(s):  
Simon Mead ◽  
R.G. Will
Keyword(s):  
Prion Disease ◽  
Prion Diseases ◽  
Mammalian Species ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Distinct Disease ◽  
Jakob Disease ◽  
Disease Variant

Prion protein (for proteinacious infectious particle) is a membrane-associated glycoprotein present in all mammalian species. Its normal function is unknown, but in prion diseases (also known as transmissible spongiform encephalopathies) a misfolded polymer form of the protein, partially resistant to protease digestion, is deposited in the brain and associated—typically after long incubation periods—with neuronal dysfunction and death. Prion diseases have become the subject of intense scientific and public interest because they are caused by a biologically distinct disease mechanism and because of the implications for public health following the identification of a new human prion disease, variant Creutzfeldt–Jakob disease (vCJD), and the evidence that it is caused by the transmission to humans of a cattle prion disease, bovine spongiform encephalopathy (BSE).

Genetic Factors in Mammalian Prion Diseases

2019 ◽  
Vol 53 (1) ◽  
pp. 117-147 ◽  
Author(s):  
Simon Mead ◽  
Sarah Lloyd ◽  
John Collinge
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Protein Interactions ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Cellular Functions ◽  
Modifying Factors ◽  
Jakob Disease ◽  
The Central Nervous System

Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene ( PRNP) and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of PRNP, whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non- PRNP factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.

scholarly journals The molecular biology of prion propagation

2001 ◽  
Vol 356 (1406) ◽  
pp. 185-195 ◽  
Author(s):  
Anthony R. Clarke ◽  
Graham S. Jackson ◽  
John Collinge
Keyword(s):  
Prion Diseases ◽  
Mammalian Species ◽  
Infectious Agent ◽  
Spongiform Encephalopathy ◽  
Conformational Isomer ◽  
Prion Propagation ◽  
Jakob Disease ◽  
Fundamental Biology ◽  
Disease Variant

Prion diseases such as Creutzfeldt–Jakob disease (CJD) in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals are associated with the accumulation in affected brains of a conformational isomer (PrP Sc ) of host–derived prion protein (PrP C ). According to the protein–only hypothesis, PrP Sc is the principal or sole component of transmissible prions. The conformational change known to be central to prion propagation, from a predominantly α–helical fold to one predominantly comprising β structure, can now be reproduced in vitro , and the ability of β–PrP to form fibrillar aggregates provides a plausible molecular mechanism for prion propagation. The existence of multiple prion strains has been difficult to explain in terms of a protein–only infectious agent but recent studies of human prion diseases suggest that strain–specific phenotypes can be encoded by different PrP conformations and glycosylation patterns. The experimental confirmation that a novel form of human prion disease, variant CJD, is caused by the same prion strain as cattle BSE, has highlighted the pressing need to understand the molecular basis of prion propagation and the transmission barriers that limit their passage between mammalian species. These and other advances in the fundamental biology of prion propagation are leading to strategies for the development of rational therapeutics.

scholarly journals Small-Molecule Theranostic Probes: A Promising Future in Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-19 ◽  
Author(s):  
Suzana Aulić ◽  
Maria Laura Bolognesi ◽  
Giuseppe Legname
Keyword(s):  
Protein Misfolding ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Infectious Agents ◽  
Wasting Disease ◽  
Imaging Probes ◽  
Jakob Disease ◽  
Misfolding Diseases ◽  
Practical Implications

Prion diseases are fatal neurodegenerative illnesses, which include Creutzfeldt-Jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. They are caused by unconventional infectious agents consisting primarily of misfolded, aggregated,β-sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (PrPC). Many lines of evidence suggest that prions (PrPSc) act both as a template for this conversion and as a neurotoxic agent causing neuronal dysfunction and cell death. As such,PrPScmay be considered as both a neuropathological hallmark of the disease and a therapeutic target. Several diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders (such as Alzheimer’s disease, Parkinson’s disease, and prion disease). Examples of these probes are Congo red, thioflavin T, and their derivatives. We synthesized a series of styryl derivatives, denoted theranostics, and studied their therapeutic and/or diagnostic potentials. Here we review the salient traits of these small molecules that are able to detect and modulate aggregated forms of several proteins involved in protein misfolding diseases. We then highlight the importance of further studies for their practical implications in therapy and diagnostics.

scholarly journals Porcine Prion Protein as a Paradigm of Limited Susceptibility to Prion Strain Propagation

2020 ◽  
Author(s):  
Juan Carlos Espinosa ◽  
Alba Marín-Moreno ◽  
Patricia Aguilar-Calvo ◽  
Sylvie L Benestad ◽  
Olivier Andreoletti ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Conformational Flexibility ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Prion Strain ◽  
Experimental Transmission ◽  
Prion Strains ◽  
Jakob Disease

Abstract Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]–Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.

scholarly journals Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice

2016 ◽  
Vol 90 (23) ◽  
pp. 10867-10874 ◽  
Author(s):  
Emilie Jaumain ◽  
Isabelle Quadrio ◽  
Laetitia Herzog ◽  
Fabienne Reine ◽  
Human Rezaei ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Diseases ◽  
Biological Properties ◽  
Causal Link ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Species Barrier ◽  
Spongiform Encephalopathies ◽  
Jakob Disease

ABSTRACTPrions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrPC) and the infecting pathological PrP assemblies (PrPSc) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrPCand in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrPScsignatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD.IMPORTANCESince the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population.

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.

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