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1
Bian, Jifeng, Vadim Khaychuk, Rachel C. Angers, Natalia Fernández-Borges, Enric Vidal, Crystal Meyerett-Reid, Sehun Kim et al. « Prion replication without host adaptation during interspecies transmissions ». Proceedings of the National Academy of Sciences 114, no 5 (17 janvier 2017) : 1141–46. http://dx.doi.org/10.1073/pnas.1611891114.
Texte intégralRésumé :
Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPCalso failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.
2
Son, Moonil, et Reed B. Wickner. « Anti-Prion Systems in Saccharomyces cerevisiae Turn an Avalanche of Prions into a Flurry ». Viruses 14, no 9 (1 septembre 2022) : 1945. http://dx.doi.org/10.3390/v14091945.
Texte intégralRésumé :
Prions are infectious proteins, mostly having a self-propagating amyloid (filamentous protein polymer) structure consisting of an abnormal form of a normally soluble protein. These prions arise spontaneously in the cell without known reason, and their effects were generally considered to be fatal based on prion diseases in humans or mammals. However, the wide array of prion studies in yeast including filamentous fungi revealed that their effects can range widely, from lethal to very mild (even cryptic) or functional, depending on the nature of the prion protein and the specific prion variant (or strain) made by the same prion protein but with a different conformation. This prion biology is affected by an array of molecular chaperone systems, such as Hsp40, Hsp70, Hsp104, and combinations of them. In parallel with the systems required for prion propagation, yeast has multiple anti-prion systems, constantly working in the normal cell without overproduction of or a deficiency in any protein, which have negative effects on prions by blocking their formation, curing many prions after they arise, preventing prion infections, and reducing the cytotoxicity produced by prions. From the protectors of nascent polypeptides (Ssb1/2p, Zuo1p, and Ssz1p) to the protein sequesterase (Btn2p), the disaggregator (Hsp104), and the mysterious Cur1p, normal levels of each can cure the prion variants arising in its absence. The controllers of mRNA quality, nonsense-mediated mRNA decay proteins (Upf1, 2, 3), can cure newly formed prion variants by association with a prion-forming protein. The regulator of the inositol pyrophosphate metabolic pathway (Siw14p) cures certain prion variants by lowering the levels of certain organic compounds. Some of these proteins have other cellular functions (e.g., Btn2), while others produce an anti-prion effect through their primary role in the normal cell (e.g., ribosomal chaperones). Thus, these anti-prion actions are the innate defense strategy against prions. Here, we outline the anti-prion systems in yeast that produce innate immunity to prions by a multi-layered operation targeting each step of prion development.
3
Watts, Joel C., Kurt Giles, Daniel J. Saltzberg, Brittany N. Dugger, Smita Patel, Abby Oehler, Sumita Bhardwaj, Andrej Sali et Stanley B. Prusiner. « Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions ». Journal of Virology 90, no 21 (20 juillet 2016) : 9558–69. http://dx.doi.org/10.1128/jvi.01106-16.
Texte intégralRésumé :
ABSTRACTThe biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrPSc, were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates.IMPORTANCEVariant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions.
4
Miller, Sarah C., Andrea K. Wegrzynowicz, Sierra J. Cole, Rachel E. Hayward, Samantha J. Ganser et Justin K. Hines. « Hsp40/JDP Requirements for the Propagation of Synthetic Yeast Prions ». Viruses 14, no 10 (30 septembre 2022) : 2160. http://dx.doi.org/10.3390/v14102160.
Texte intégralRésumé :
Yeast prions are protein-based transmissible elements, most of which are amyloids. The chaperone protein network in yeast is inexorably linked to the spreading of prions during cell division by fragmentation of amyloid prion aggregates. Specifically, the core “prion fragmentation machinery” includes the proteins Hsp104, Hsp70 and the Hsp40/J-domain protein (JDP) Sis1. Numerous novel amyloid-forming proteins have been created and examined in the yeast system and occasionally these amyloids are also capable of continuous Hsp104-dependent propagation in cell populations, forming synthetic prions. However, additional chaperone requirements, if any, have not been determined. Here, we report the first instances of a JDP-Hsp70 system requirement for the propagation of synthetic prions. We utilized constructs from a system of engineered prions with prion-forming domains (PrDs) consisting of a polyQ stretch interrupted by a single heterologous amino acid interspersed every fifth residue. These “polyQX” PrDs are fused to the MC domains of Sup35, creating chimeric proteins of which a subset forms synthetic prions in yeast. For four of these prions, we show that SIS1 repression causes prion loss in a manner consistent with Sis1′s known role in prion fragmentation. PolyQX prions were sensitive to Sis1 expression levels to differing degrees, congruent with the variability observed among native prions. Our results expand the scope known Sis1 functionality, demonstrating that Sis1 acts on amyloids broadly, rather than through specific protein–protein interactions with individual yeast prion-forming proteins.
5
Krauss, Sybille, et Ina Vorberg. « PrionsEx Vivo : What Cell Culture Models Tell Us about Infectious Proteins ». International Journal of Cell Biology 2013 (2013) : 1–14. http://dx.doi.org/10.1155/2013/704546.
Texte intégralRésumé :
Prions are unconventional infectious agents that are composed of misfolded aggregated prion protein. Prions replicate their conformation by template-assisted conversion of the endogenous prion protein PrP. Templated conversion of soluble proteins into protein aggregates is also a hallmark of other neurodegenerative diseases. Alzheimer’s disease or Parkinson’s disease are not considered infectious diseases, although aggregate pathology appears to progress in a stereotypical fashion reminiscent of the spreading behavior ofmammalian prions. While basic principles of prion formation have been studied extensively, it is still unclear what exactly drives PrP molecules into an infectious, self-templating conformation. In this review, we discuss crucial steps in the life cycle of prions that have been revealed inex vivomodels. Importantly, the persistent propagation of prions in mitotically active cells argues that cellular processes are in place that not only allow recruitment of cellular PrP into growing prion aggregates but also enable the multiplication of infectious seeds that are transmitted to daughter cells. Comparison of prions with other protein aggregates demonstrates that not all the characteristics of prions are equally shared by prion-like aggregates. Future experiments may reveal to which extent aggregation-prone proteins associated with other neurodegenerative diseases can copy the replication strategies of prions.
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Krejciova, Zuzana, James Alibhai, Chen Zhao, Robert Krencik, Nina M. Rzechorzek, Erik M. Ullian, Jean Manson, James W. Ironside, Mark W. Head et Siddharthan Chandran. « Human stem cell–derived astrocytes replicate human prions in a PRNP genotype–dependent manner ». Journal of Experimental Medicine 214, no 12 (15 novembre 2017) : 3481–95. http://dx.doi.org/10.1084/jem.20161547.
Texte intégralRésumé :
Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype–dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery.
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Tahir, Waqas, Basant Abdulrahman, Dalia H. Abdelaziz, Simrika Thapa, Rupali Walia et Hermann M. Schätzl. « An astrocyte cell line that differentially propagates murine prions ». Journal of Biological Chemistry 295, no 33 (19 juin 2020) : 11572–83. http://dx.doi.org/10.1074/jbc.ra120.012596.
Texte intégralRésumé :
Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the pathological isoform PrPSc. Elucidating the molecular and cellular mechanisms underlying prion propagation may help to develop disease interventions. Cell culture systems for prion propagation have greatly advanced molecular insights into prion biology, but translation of in vitro to in vivo findings is often disappointing. A wider range of cell culture systems might help overcome these shortcomings. Here, we describe an immortalized mouse neuronal astrocyte cell line (C8D1A) that can be infected with murine prions. Both PrPC protein and mRNA levels in astrocytes were comparable with those in neuronal and non-neuronal cell lines permitting persistent prion infection. We challenged astrocytes with three mouse-adapted prion strains (22L, RML, and ME7) and cultured them for six passages. Immunoblotting results revealed that the astrocytes propagated 22L prions well over all six passages, whereas ME7 prions did not replicate, and RML prions replicated only very weakly after five passages. Immunofluorescence analysis indicated similar results for PrPSc. Interestingly, when we used prion conversion activity as a readout in real-time quaking-induced conversion assays with RML-infected cell lysates, we observed a strong signal over all six passages, comparable with that for 22L-infected cells. These data indicate that the C8D1A cell line is permissive to prion infection. Moreover, the propagated prions differed in conversion and proteinase K–resistance levels in these astrocytes. We propose that the C8D1A cell line could be used to decipher prion strain biology.
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Safar, Jiri G., Klaus Kellings, Ana Serban, Darlene Groth, James E. Cleaver, Stanley B. Prusiner et Detlev Riesner. « Search for a Prion-Specific Nucleic Acid ». Journal of Virology 79, no 16 (15 août 2005) : 10796–806. http://dx.doi.org/10.1128/jvi.79.16.10796-10806.2005.
Texte intégralRésumé :
ABSTRACT Diversity of prion strains was attributed to an elusive nucleic acid, yet a search spanning nearly two decades has failed to identify a prion-specific polynucleotide. In our search for a prion-specific nucleic acid, we analyzed nucleic acids in purified fractions from the brains of Syrian hamsters infected with Sc237 prions. Purification of Sc237 prions removed nucleic acids larger than 50 nucleotides as measured by return refocusing electrophoresis (RRGE). To determine the size of the largest polynucleotide present in purified fractions at an abundance of one molecule per infectious (ID50) unit, we measured prions present after inoculation. In order to account for the rapid clearance of prions after intracerebral inoculation, we determined the number of PrPSc molecules and ID50 units of prions that were retained in brain. Factoring in clearance after inoculation, we estimate that the largest polynucleotide present in our purified fractions at one molecule per ID50 unit is ≈25 nucleotides in length. In the same fractions, there were ≈3,000 protease-resistant PrPSc molecules per ID50 unit after accounting for clearance of PrPSc following inoculation. We compared the resistance of Sc237 and 139H prions to inactivation by UV irradiation at 254 nm. Irradiation of homogenates and microsomes diminished prion infectivity by a factor of ≈1,000 but did not alter the strain-specified properties of the Sc237 and 139H prions. The data reported here combined with the production of synthetic prions argue that the 25-mer polynucleotides found in purified prion preparations are likely to be host encoded and of variable sequence; additionally, these 25-mers are unlikely to be prion specific.
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Evarts, Jacob, et Mikala Capage. « Hunting for Prions : Propagating Putative Prion States in Budding Yeast ». Oregon Undergraduate Research Journal 18, no 1 (2021) : 26–34. http://dx.doi.org/10.5399/uo/ourj/18.1.4.
Texte intégralRésumé :
Prions have been closely associated with fatal neurodegenerative diseases. Recent evidence, however, suggests that prions also represent an additional class of epigenetic mechanism that is biologically beneficial. From an evolutionary standpoint, the ability to change phenotypes without requiring changes to the genome, as prions do, would be hugely beneficial in fluctuating environments. Through overexpressing proteins and introducing environmental stressors, two techniques known to increase de novo prion formation, we performed a large-scale screen of many RNA-modifying enzymes in budding yeast to test if they harbor beneficial prionogenic behavior. From this screen, six induced prion-like states were found to be mitotically stable and infectious. We show that many of these putative prions are dominant and are dependent on chaperone proteins, which is consistent with a prion-based epigenetic mechanism. Prion-based inheritance is expanding on the central dogma of biology, contributing to the belief that prions work as an epigenetic mechanism for passing on heritable traits.
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Terry, Cassandra, Adam Wenborn, Nathalie Gros, Jessica Sells, Susan Joiner, Laszlo L. P. Hosszu, M. Howard Tattum et al. « Ex vivo mammalian prions are formed of paired double helical prion protein fibrils ». Open Biology 6, no 5 (mai 2016) : 160035. http://dx.doi.org/10.1098/rsob.160035.
Texte intégralRésumé :
Mammalian prions are hypothesized to be fibrillar or amyloid forms of prion protein (PrP), but structures observed to date have not been definitively correlated with infectivity and the three-dimensional structure of infectious prions has remained obscure. Recently, we developed novel methods to obtain exceptionally pure preparations of prions from mouse brain and showed that pathogenic PrP in these high-titre preparations is assembled into rod-like assemblies. Here, we have used precise cell culture-based prion infectivity assays to define the physical relationship between the PrP rods and prion infectivity and have used electron tomography to define their architecture. We show that infectious PrP rods isolated from multiple prion strains have a common hierarchical assembly comprising twisted pairs of short fibres with repeating substructure. The architecture of the PrP rods provides a new structural basis for understanding prion infectivity and can explain the inability to systematically generate high-titre synthetic prions from recombinant PrP.
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Uchiyama, Keiji, Hideyuki Hara, Junji Chida, Agriani Dini Pasiana, Morikazu Imamura, Tsuyoshi Mori, Hanae Takatsuki, Ryuichiro Atarashi et Suehiro Sakaguchi. « Ethanolamine Is a New Anti-Prion Compound ». International Journal of Molecular Sciences 22, no 21 (29 octobre 2021) : 11742. http://dx.doi.org/10.3390/ijms222111742.
Texte intégralRésumé :
Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrPSc. PrPSc is produced through conformational conversion of the cellular isoform of prion protein, PrPC, in the brain. To date, no effective therapies for prion diseases have been developed. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrPSc levels when cultured in advanced Dulbecco’s modified eagle medium (DMEM) but not in classic DMEM. PrPC levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrPSc levels in N2aC24L1-3 cells, but not PrPC levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound.
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Groener, Albrecht, Wolfram Schäfer, Henry Baron et Martin Vey. « Hamster Prions Are a Suitable Model for Partitioning of Human CJD Prions during Plasma Processing Steps. » Blood 104, no 11 (16 novembre 2004) : 3644. http://dx.doi.org/10.1182/blood.v104.11.3644.3644.
Texte intégralRésumé :
Abstract Prion removal evaluation of plasma processing procedures is one important basis to assess the margin of safety of plasma protein therapeutics. Currently, in these evaluation studies to assess the removal capacity of selected manufacturing steps for human prions mainly prions derived from scrapie-infected hamsters or mice are used in spiking studies. In order to test the validity of hamster prions instead of different human prion strains as spiking reagents, we compared the partitioning of these prion preparations at two purification steps common to the manufacturing of several human plasma-derived therapeutic proteins at ZLB Behring. The glycine precipitation (inherent in the manufacture of e.g., vWF/Factor VIII) and the 25% ethanol precipitation step (inherent in the manufacture of e.g., alpha-1-proteinase inhibitor and albumin) were down scaled to mimic the production process. A microsomal membrane preparation as well as purified full-length pathogenic prion (PrPSc; without membrane association) prepared (a) from hamster brains infected with the model scrapie strain Sc237, (b) from brains of transgenic mice infected with human sporadic CJD prions, and (c) from the brain of a patient who died of vCJD were used for spiking experiments. The different prion preparations were spiked to the starting material of the manufacturing steps studied and the manufacturing step was performed in a dedicated laboratory. The amount of PrPSc in all fractions was determined quantitatively utilizing an ELISA-formatted Conformation Dependent Immunoassay [Safar et al., Nat Med1998; 41157–1165]. The 25% ethanol precipitation removed very effectively all prion preparations equally regardless of their origin (reduction factor ≥ 3 log10). The glycine precipitation removed the microsomal as well as the purified prion preparations from all species equally whereby prions of the purified prion preparation were removed to a considerably higher degree than the membrane preparation (reduction factor ≥ 3 log10 vs. 1.6 to 1.8 log10). In parallel, prion infectivity of each sample is currently tested in animal bioassays involving transgenic mice susceptible for the tested prion strain. It can be concluded, up to now based on immunological data, that spiked hamster prions are a reliable model to confirm the safety of human plasma-derived products also for human derived prions.
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Barbitoff, Yury A., Andrew G. Matveenko et Galina A. Zhouravleva. « Differential Interactions of Molecular Chaperones and Yeast Prions ». Journal of Fungi 8, no 2 (27 janvier 2022) : 122. http://dx.doi.org/10.3390/jof8020122.
Texte intégralRésumé :
Baker’s yeast Saccharomyces cerevisiae is an important model organism that is applied to study various aspects of eukaryotic cell biology. Prions in yeast are self-perpetuating heritable protein aggregates that can be leveraged to study the interaction between the protein quality control (PQC) machinery and misfolded proteins. More than ten prions have been identified in yeast, of which the most studied ones include [PSI+], [URE3], and [PIN+]. While all of the major molecular chaperones have been implicated in propagation of yeast prions, many of these chaperones differentially impact propagation of different prions and/or prion variants. In this review, we summarize the current understanding of the life cycle of yeast prions and systematically review the effects of different chaperone proteins on their propagation. Our analysis clearly shows that Hsp40 proteins play a central role in prion propagation by determining the fate of prion seeds and other amyloids. Moreover, direct prion-chaperone interaction seems to be critically important for proper recruitment of all PQC components to the aggregate. Recent results also suggest that the cell asymmetry apparatus, cytoskeleton, and cell signaling all contribute to the complex network of prion interaction with the yeast cell.
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Jheeta, Sohan, Elias Chatzitheodoridis, Kevin Devine et Janice Block. « The Way forward for the Origin of Life : Prions and Prion-Like Molecules First Hypothesis ». Life 11, no 9 (25 août 2021) : 872. http://dx.doi.org/10.3390/life11090872.
Texte intégralRésumé :
In this paper the hypothesis that prions and prion-like molecules could have initiated the chemical evolutionary process which led to the eventual emergence of life is reappraised. The prions first hypothesis is a specific application of the protein-first hypothesis which asserts that protein-based chemical evolution preceded the evolution of genetic encoding processes. This genetics-first hypothesis asserts that an “RNA-world era” came before protein-based chemical evolution and rests on a singular premise that molecules such as RNA, acetyl-CoA, and NAD are relics of a long line of chemical evolutionary processes preceding the Last Universal Common Ancestor (LUCA). Nevertheless, we assert that prions and prion-like molecules may also be relics of chemical evolutionary processes preceding LUCA. To support this assertion is the observation that prions and prion-like molecules are involved in a plethora of activities in contemporary biology in both complex (eukaryotes) and primitive life forms. Furthermore, a literature survey reveals that small RNA virus genomes harbor information about prions (and amyloids). If, as has been presumed by proponents of the genetics-first hypotheses, small viruses were present during an RNA world era and were involved in some of the earliest evolutionary processes, this places prions and prion-like molecules potentially at the heart of the chemical evolutionary process whose eventual outcome was life. We deliberate on the case for prions and prion-like molecules as the frontier molecules at the dawn of evolution of living systems.
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Mathur, Vidhu, Vibha Taneja, Yidi Sun et Susan W. Liebman. « Analyzing the Birth and Propagation of Two Distinct Prions, [PSI+] and [Het-s]y, in Yeast ». Molecular Biology of the Cell 21, no 9 (mai 2010) : 1449–61. http://dx.doi.org/10.1091/mbc.e09-11-0927.
Texte intégralRésumé :
Various proteins, like the infectious yeast prions and the noninfectious human Huntingtin protein (with expanded polyQ), depend on a Gln or Asn (QN)-rich region for amyloid formation. Other prions, e.g., mammalian PrP and the [Het-s] prion of Podospora anserina, although still able to form infectious amyloid aggregates, do not have QN-rich regions. Furthermore, [Het-s] and yeast prions appear to differ dramatically in their amyloid conformation. Despite these differences, a fusion of the Het-s prion domain to GFP (Het-sPrD-GFP) can propagate in yeast as a prion called [Het-s]y. We analyzed the properties of two divergent prions in yeast: [Het-s]y and the native yeast prion [PSI+] (prion form of translational termination factor Sup35). Curiously, the induced appearance and transmission of [PSI+] and [Het-s]y aggregates is remarkably similar. Overexpression of tagged prion protein (Sup35-GFP or Het-sPrD-GFP) in nonprion cells gives rise to peripheral, and later internal, ring/mesh-like aggregates. The cells with these ring-like aggregates give rise to daughters with one (perivacuolar) or two (perivacuolar and juxtanuclear) dot-like aggregates per cell. These line, ring, mesh, and dot aggregates are not really the transmissible prion species and should only be regarded as phenotypic markers of the presence of the prions. Both [PSI+] and [Het-s]y first appear in daughters as numerous tiny dot-like aggregates, and both require the endocytic protein, Sla2, for ring formation, but not propagation.
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Jack, Kezia, Graham S. Jackson et Jan Bieschke. « Essential Components of Synthetic Infectious Prion Formation De Novo ». Biomolecules 12, no 11 (16 novembre 2022) : 1694. http://dx.doi.org/10.3390/biom12111694.
Texte intégralRésumé :
Prion diseases are a class of neurodegenerative diseases that are uniquely infectious. Whilst their general replication mechanism is well understood, the components required for the formation and propagation of highly infectious prions are poorly characterized. The protein-only hypothesis posits that the prion protein (PrP) is the only component of the prion; however, additional co-factors are required for its assembly into infectious prions. These can be provided by brain homogenate, but synthetic lipids and non-coding RNA have also been used in vitro. Here, we review a range of experimental approaches, which generate PrP amyloid assemblies de novo. These synthetic PrP assemblies share some, but not necessarily all, properties of genuine infectious prions. We will discuss the different experimental approaches, how a prion is defined, the non-protein requirements of a prion, and provide an overview of the current state of prion amplification and generation in vitro.
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Vorberg, Ina M. « All the Same ? The Secret Life of Prion Strains within Their Target Cells ». Viruses 11, no 4 (9 avril 2019) : 334. http://dx.doi.org/10.3390/v11040334.
Texte intégralRésumé :
Prions are infectious β-sheet-rich protein aggregates composed of misfolded prion protein (PrPSc) that do not possess coding nucleic acid. Prions replicate by recruiting and converting normal cellular PrPC into infectious isoforms. In the same host species, prion strains target distinct brain regions and cause different disease phenotypes. Prion strains are associated with biophysically distinct PrPSc conformers, suggesting that strain properties are enciphered within alternative PrPSc quaternary structures. So far it is unknown how prion strains target specific cells and initiate productive infections. Deeper mechanistic insight into the prion life cycle came from cell lines permissive to a range of different prion strains. Still, it is unknown why certain cell lines are refractory to infection by one strain but permissive to another. While pharmacologic and genetic manipulations revealed subcellular compartments involved in prion replication, little is known about strain-specific requirements for endocytic trafficking pathways. This review summarizes our knowledge on how prions replicate within their target cells and on strain-specific differences in prion cell biology.
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Wälzlein, Joo-Hee, Karla A. Schwenke et Michael Beekes. « Propagation of CJD Prions in Primary Murine Glia Cells Expressing Human PrPc ». Pathogens 10, no 8 (20 août 2021) : 1060. http://dx.doi.org/10.3390/pathogens10081060.
Texte intégralRésumé :
There are various existing cell models for the propagation of animal prions. However, in vitro propagation of human prions has been a long-standing challenge. This study presents the establishment of a long-term primary murine glia culture expressing the human prion protein homozygous for methionine at codon 129, which allows in vitro propagation of Creutzfeldt–Jakob disease (CJD) prions (variant CJD (vCJD) and sporadic CJD (sCJD) type MM2). Prion propagation could be detected by Western blotting of pathological proteinase K-resistant prion protein (PrPSc) from 120 days post exposure. The accumulation of PrPSc could be intensified by adding a cationic lipid mixture to the infectious brain homogenate at the time of infection. Stable propagation of human prions in a long-term murine glia cell culture represents a new tool for future drug development and for mechanistic studies in the field of human prion biology. In addition, our cell model can reduce the need for bioassays with human prions and thereby contributes to further implementation of the 3R principles aiming at replacement, reduction and refinement of animal experiments.
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Benilova, Iryna, Madeleine Reilly, Cassandra Terry, Adam Wenborn, Christian Schmidt, Aline T. Marinho, Emmanuel Risse et al. « Highly infectious prions are not directly neurotoxic ». Proceedings of the National Academy of Sciences 117, no 38 (8 septembre 2020) : 23815–22. http://dx.doi.org/10.1073/pnas.2007406117.
Texte intégralRésumé :
Prions are infectious agents which cause rapidly lethal neurodegenerative diseases in humans and animals following long, clinically silent incubation periods. They are composed of multichain assemblies of misfolded cellular prion protein. While it has long been assumed that prions are themselves neurotoxic, recent development of methods to obtain exceptionally pure prions from mouse brain with maintained strain characteristics, and in which defined structures—paired rod-like double helical fibers—can be definitively correlated with infectivity, allowed a direct test of this assertion. Here we report that while brain homogenates from symptomatic prion-infected mice are highly toxic to cultured neurons, exceptionally pure intact high-titer infectious prions are not directly neurotoxic. We further show that treatment of brain homogenates from prion-infected mice with sodium lauroylsarcosine destroys toxicity without diminishing infectivity. This is consistent with models in which prion propagation and toxicity can be mechanistically uncoupled.
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Peretz, David, Surachai Supattapone, Kurt Giles, Julie Vergara, Yevgeniy Freyman, Pierre Lessard, Jiri G. Safar et al. « Inactivation of Prions by Acidic Sodium Dodecyl Sulfate ». Journal of Virology 80, no 1 (1 janvier 2006) : 322–31. http://dx.doi.org/10.1128/jvi.80.1.322-331.2006.
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ABSTRACT Prompted by the discovery that prions become protease-sensitive after exposure to branched polyamine dendrimers in acetic acid (AcOH) (S. Supattapone, H. Wille, L. Uyechi, J. Safar, P. Tremblay, F. C. Szoka, F. E. Cohen, S. B. Prusiner, and M. R. Scott, J. Virol. 75:3453-3461, 2001), we investigated the inactivation of prions by sodium dodecyl sulfate (SDS) in weak acid. As judged by sensitivity to proteolytic digestion, the disease-causing prion protein (PrPSc) was denatured at room temperature by SDS at pH values of ≤4.5 or ≥10. Exposure of Sc237 prions in Syrian hamster brain homogenates to 1% SDS and 0.5% AcOH at room temperature resulted in a reduction of prion titer by a factor of ca. 107; however, all of the bioassay hamsters eventually developed prion disease. When various concentrations of SDS and AcOH were tested, the duration and temperature of exposure acted synergistically to inactivate both hamster Sc237 prions and human sporadic Creutzfeldt-Jakob disease (sCJD) prions. The inactivation of prions in brain homogenates and those bound to stainless steel wires was evaluated by using bioassays in transgenic mice. sCJD prions were more than 100,000 times more resistant to inactivation than Sc237 prions, demonstrating that inactivation procedures validated on rodent prions cannot be extrapolated to inactivation of human prions. Some procedures that significantly reduced prion titers in brain homogenates had a limited effect on prions bound to the surface of stainless steel wires. Using acidic SDS combined with autoclaving for 15 min, human sCJD prions bound to stainless steel wires were eliminated. Our findings form the basis for a noncorrosive system that is suitable for inactivating prions on surgical instruments, as well as on other medical and dental equipment.
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Wickner, Reed B., Herman K. Edskes, Moonil Son et Songsong Wu. « Anti-Prion Systems Block Prion Transmission, Attenuate Prion Generation, Cure Most Prions as They Arise and Limit Prion-Induced Pathology in Saccharomyces cerevisiae ». Biology 11, no 9 (26 août 2022) : 1266. http://dx.doi.org/10.3390/biology11091266.
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All variants of the yeast prions [PSI+] and [URE3] are detrimental to their hosts, as shown by the dramatic slowing of growth (or even lethality) of a majority, by the rare occurrence in wild isolates of even the mildest variants and by the absence of reproducible benefits of these prions. To deal with the prion problem, the host has evolved an array of anti-prion systems, acting in normal cells (without overproduction or deficiency of any component) to block prion transmission from other cells, to lower the rates of spontaneous prion generation, to cure most prions as they arise and to limit the damage caused by those variants that manage to elude these (necessarily) imperfect defenses. Here we review the properties of prion protein sequence polymorphisms Btn2, Cur1, Hsp104, Upf1,2,3, ribosome-associated chaperones, inositol polyphosphates, Sis1 and Lug1, which are responsible for these anti-prion effects. We recently showed that the combined action of ribosome-associated chaperones, nonsense-mediated decay factors and the Hsp104 disaggregase lower the frequency of [PSI+] appearance as much as 5000-fold. Moreover, while Btn2 and Cur1 are anti-prion factors against [URE3] and an unrelated artificial prion, they promote [PSI+] prion generation and propagation.
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Wickner, Reed, Moonil Son et Herman Edskes. « Prion Variants of Yeast are Numerous, Mutable, and Segregate on Growth, Affecting Prion Pathogenesis, Transmission Barriers, and Sensitivity to Anti-Prion Systems ». Viruses 11, no 3 (9 mars 2019) : 238. http://dx.doi.org/10.3390/v11030238.
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The known amyloid-based prions of Saccharomyces cerevisiae each have multiple heritable forms, called “prion variants” or “prion strains”. These variants, all based on the same prion protein sequence, differ in their biological properties and their detailed amyloid structures, although each of the few examined to date have an in-register parallel folded β sheet architecture. Here, we review the range of biological properties of yeast prion variants, factors affecting their generation and propagation, the interaction of prion variants with each other, the mutability of prions, and their segregation during mitotic growth. After early differentiation between strong and weak stable and unstable variants, the parameters distinguishing the variants has dramatically increased, only occasionally correlating with the strong/weak paradigm. A sensitivity to inter- and intraspecies barriers, anti-prion systems, and chaperone deficiencies or excesses and other factors all have dramatic selective effects on prion variants. Recent studies of anti-prion systems, which cure prions in wild strains, have revealed an enormous array of new variants, normally eliminated as they arise and so not previously studied. This work suggests that defects in the anti-prion systems, analogous to immune deficiencies, may be at the root of some human amyloidoses.
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Thapa, Simrika, Cristobal Marrero Winkens, Waqas Tahir, Maria I. Arifin, Sabine Gilch et Hermann M. Schatzl. « Gene-Edited Cell Models to Study Chronic Wasting Disease ». Viruses 14, no 3 (15 mars 2022) : 609. http://dx.doi.org/10.3390/v14030609.
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Prion diseases are fatal infectious neurodegenerative disorders affecting both humans and animals. They are caused by the misfolded isoform of the cellular prion protein (PrPC), PrPSc, and currently no options exist to prevent or cure prion diseases. Chronic wasting disease (CWD) in deer, elk and other cervids is considered the most contagious prion disease, with extensive shedding of infectivity into the environment. Cell culture models provide a versatile platform for convenient quantification of prions, for studying the molecular and cellular biology of prions, and for performing high-throughput screening of potential therapeutic compounds. Unfortunately, only a very limited number of cell lines are available that facilitate robust and persistent propagation of CWD prions. Gene-editing using programmable nucleases (e.g., CRISPR-Cas9 (CC9)) has proven to be a valuable tool for high precision site-specific gene modification, including gene deletion, insertion, and replacement. CC9-based gene editing was used recently for replacing the PrP gene in mouse and cell culture models, as efficient prion propagation usually requires matching sequence homology between infecting prions and prion protein in the recipient host. As expected, such gene-editing proved to be useful for developing CWD models. Several transgenic mouse models were available that propagate CWD prions effectively, however, mostly fail to reproduce CWD pathogenesis as found in the cervid host, including CWD prion shedding. This is different for the few currently available knock-in mouse models that seem to do so. In this review, we discuss the available in vitro and in vivo models of CWD, and the impact of gene-editing strategies.
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Hannaoui, Samia, Elizabeth Triscott, Camilo Duque Velásquez, Sheng Chun Chang, Maria Immaculata Arifin, Irina Zemlyankina, Xinli Tang et al. « New and distinct chronic wasting disease strains associated with cervid polymorphism at codon 116 of the Prnp gene ». PLOS Pathogens 17, no 7 (26 juillet 2021) : e1009795. http://dx.doi.org/10.1371/journal.ppat.1009795.
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Chronic wasting disease (CWD) is a prion disease affecting cervids. Polymorphisms in the prion protein gene can result in extended survival of CWD-infected animals. However, the impact of polymorphisms on cellular prion protein (PrPC) and prion properties is less understood. Previously, we characterized the effects of a polymorphism at codon 116 (A>G) of the white-tailed deer (WTD) prion protein and determined that it destabilizes PrPC structure. Comparing CWD isolates from WTD expressing homozygous wild-type (116AA) or heterozygous (116AG) PrP, we found that 116AG-prions were conformationally less stable, more sensitive to proteases, with lower seeding activity in cell-free conversion and reduced infectivity. Here, we aimed to understand CWD strain emergence and adaptation. We show that the WTD-116AG isolate contains two different prion strains, distinguished by their host range, biochemical properties, and pathogenesis from WTD-116AA prions (Wisc-1). Serial passages of WTD-116AG prions in tg(CerPrP)1536+/+ mice overexpressing wild-type deer-PrPC revealed two populations of mice with short and long incubation periods, respectively, and remarkably prolonged clinical phase upon inoculation with WTD-116AG prions. Inoculation of serially diluted brain homogenates confirmed the presence of two strains in the 116AG isolate with distinct pathology in the brain. Interestingly, deglycosylation revealed proteinase K-resistant fragments with different electrophoretic mobility in both tg(CerPrP)1536+/+ mice and Syrian golden hamsters infected with WTD-116AG. Infection of tg60 mice expressing deer S96-PrP with 116AG, but not Wisc-1 prions induced clinical disease. On the contrary, bank voles resisted 116AG prions, but not Wisc-1 infection. Our data indicate that two strains co-existed in the WTD-116AG isolate, expanding the variety of CWD prion strains. We argue that the 116AG isolate does not contain Wisc-1 prions, indicating that the presence of 116G-PrPC diverted 116A-PrPC from adopting a Wisc-1 structure. This can have important implications for their possible distinct capacities to cross species barriers into both cervids and non-cervids.
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Woerman, Amanda L., Jan Stöhr, Atsushi Aoyagi, Ryan Rampersaud, Zuzana Krejciova, Joel C. Watts, Takao Ohyama et al. « Propagation of prions causing synucleinopathies in cultured cells ». Proceedings of the National Academy of Sciences 112, no 35 (18 août 2015) : E4949—E4958. http://dx.doi.org/10.1073/pnas.1513426112.
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Increasingly, evidence argues that many neurodegenerative diseases, including progressive supranuclear palsy (PSP), are caused by prions, which are alternatively folded proteins undergoing self-propagation. In earlier studies, PSP prions were detected by infecting human embryonic kidney (HEK) cells expressing a tau fragment [TauRD(LM)] fused to yellow fluorescent protein (YFP). Here, we report on an improved bioassay using selective precipitation of tau prions from human PSP brain homogenates before infection of the HEK cells. Tau prions were measured by counting the number of cells with TauRD(LM)–YFP aggregates using confocal fluorescence microscopy. In parallel studies, we fused α-synuclein to YFP to bioassay α-synuclein prions in the brains of patients who died of multiple system atrophy (MSA). Previously, MSA prion detection required ∼120 d for transmission into transgenic mice, whereas our cultured cell assay needed only 4 d. Variation in MSA prion levels in four different brain regions from three patients provided evidence for three different MSA prion strains. Attempts to demonstrate α-synuclein prions in brain homogenates from Parkinson’s disease patients were unsuccessful, identifying an important biological difference between the two synucleinopathies. Partial purification of tau and α-synuclein prions facilitated measuring the levels of these protein pathogens in human brains. Our studies should facilitate investigations of the pathogenesis of both tau and α-synuclein prion disorders as well as help decipher the basic biology of those prions that attack the CNS.
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Bosque, Patrick J., et Stanley B. Prusiner. « Cultured Cell Sublines Highly Susceptible to Prion Infection ». Journal of Virology 74, no 9 (1 mai 2000) : 4377–86. http://dx.doi.org/10.1128/jvi.74.9.4377-4386.2000.
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ABSTRACT Cultured cell lines infected with prions produce an abnormal isoform of the prion protein (PrPSc). In order to derive cell lines producing sufficient quantities of PrPSc for most studies, it has been necessary to subclone infected cultures and select the subclones producing the largest amounts of PrPSc. Since postinfection cloning can introduce differences between infected and uninfected cell lines, we sought an approach to generate prion-infected cell lines that would avoid clonal artifacts. Using an improved cell blot technique, which permits sensitive and rapid comparison of PrPSc levels in multiple independent cell cultures, we discovered marked heterogeneity with regard to prion susceptibility in tumor cell sublines. We exploited this heterogeneity to derive sublines which are highly susceptible to prion infection and used these cells to generate prion-infected lines without further subcloning. These infected sublines can be compared to the cognate uninfected cultures without interference from cloning artifacts. We also used susceptible cell lines and our modified cell blot procedure to develop a sensitive and reproducible quantitative cell culture bioassay for prions. We found that the sublines were at least 100-fold more susceptible to strain RML prions than to strain ME7 prions. Comparisons between scrapie-susceptible and -resistant cell lines may reveal factors that modulate prion propagation.
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Barry, R. A., M. P. McKinley, P. E. Bendheim, G. K. Lewis, S. J. DeArmond et S. B. Prusiner. « Antibodies to the scrapie protein decorate prion rods. » Journal of Immunology 135, no 1 (1 juillet 1985) : 603–13. http://dx.doi.org/10.4049/jimmunol.135.1.603.
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Abstract Scrapie is a degenerative, transmissible neurologic disease of sheep and goats which occurs in the absence of any detectable host immune response. Antibodies to the scrapie agent have been produced after immunization of rabbits with either scrapie prions or the prion protein, PrP 27-30, purified from infected hamster brain. Immunoreactivity of the antisera was assessed by dot and Western immunoblots with purified prions and PrP 27-30. Antibodies raised against infectious prions were more immunoreactive with native than denatured preparations, whereas those raised against PrP 27-30 were more reactive with denatured prion preparations. As determined by second antibody-colloidal gold, both antisera were found to decorate scrapie prion rods in purified preparations. Antibodies to cellular filamentous proteins failed to react with PrP 27-30 or the scrapie prion rods; conversely, antibodies to PrP 27-30 did not exhibit immunoreactivity with cellular filamentous proteins. The monospecificity of the rabbit antiserum raised against PrP 27-30 was established by its reactivity after affinity purification. The purified antibodies reacted with PrP 27-30 on Western blots and with the prion rods. Considerable evidence indicates that the scrapie rods are aggregates of infectious prions; the findings presented here provide an immunologic demonstration that PrP 27-30 is a structural component of the prion rods.
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Kang, Hae-Eun, Youngwon Mo, Raihah Abd Rahim, Hye-Mi Lee et Chongsuk Ryou. « Prion Diagnosis : Application of Real-Time Quaking-Induced Conversion ». BioMed Research International 2017 (2017) : 1–8. http://dx.doi.org/10.1155/2017/5413936.
Texte intégralRésumé :
Prions composed of pathogenic scrapie prion protein (PrPSc) are infectious pathogens that cause progressive neurological conditions known as prion diseases or transmissible spongiform encephalopathies. Although these diseases pose considerable risk to public health, procedures for early diagnosis have not been established. One of the most recent attempts at sensitive and specific detection of prions is the real-time quaking-induced conversion (RT-QuIC) method, which measures the activity of PrPScaggregates or amyloid formation triggered by PrPScseeds in the presence of recombinant PrP. In this review, we summarize prions, prion diseases, and current approaches to diagnosis, including the principle, conditions for assay performance, and current diagnostic applications of RT-QuIC.
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Herbst, Allen, Serene Wohlgemuth, Jing Yang, Andrew R. Castle, Diana Martinez Moreno, Alicia Otero, Judd M. Aiken, David Westaway et Debbie McKenzie. « Susceptibility of Beavers to Chronic Wasting Disease ». Biology 11, no 5 (26 avril 2022) : 667. http://dx.doi.org/10.3390/biology11050667.
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Chronic wasting disease (CWD) is a contagious, fatal, neurodegenerative prion disease of cervids. The expanding geographical range and rising prevalence of CWD are increasing the risk of pathogen transfer and spillover of CWD to non-cervid sympatric species. As beavers have close contact with environmental and food sources of CWD infectivity, we hypothesized that they may be susceptible to CWD prions. We evaluated the susceptibility of beavers to prion diseases by challenging transgenic mice expressing beaver prion protein (tgBeaver) with five strains of CWD, four isolates of rodent-adapted prions and one strain of Creutzfeldt–Jakob disease. All CWD strains transmitted to the tgBeaver mice, with attack rates highest from moose CWD and the 116AG and H95+ strains of deer CWD. Mouse-, rat-, and especially hamster-adapted prions were also transmitted with complete attack rates and short incubation periods. We conclude that the beaver prion protein is an excellent substrate for sustaining prion replication and that beavers are at risk for CWD pathogen transfer and spillover.
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Herbst, Allen, Serene Wohlgemuth, Jing Yang, Andrew R. Castle, Diana Martinez Moreno, Alicia Otero, Judd M. Aiken, David Westaway et Debbie McKenzie. « Susceptibility of Beavers to Chronic Wasting Disease ». Biology 11, no 5 (26 avril 2022) : 667. http://dx.doi.org/10.3390/biology11050667.
Texte intégralRésumé :
Chronic wasting disease (CWD) is a contagious, fatal, neurodegenerative prion disease of cervids. The expanding geographical range and rising prevalence of CWD are increasing the risk of pathogen transfer and spillover of CWD to non-cervid sympatric species. As beavers have close contact with environmental and food sources of CWD infectivity, we hypothesized that they may be susceptible to CWD prions. We evaluated the susceptibility of beavers to prion diseases by challenging transgenic mice expressing beaver prion protein (tgBeaver) with five strains of CWD, four isolates of rodent-adapted prions and one strain of Creutzfeldt–Jakob disease. All CWD strains transmitted to the tgBeaver mice, with attack rates highest from moose CWD and the 116AG and H95+ strains of deer CWD. Mouse-, rat-, and especially hamster-adapted prions were also transmitted with complete attack rates and short incubation periods. We conclude that the beaver prion protein is an excellent substrate for sustaining prion replication and that beavers are at risk for CWD pathogen transfer and spillover.
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Asante, Emmanuel A., Ian Gowland, Andrew Grimshaw, Jacqueline M. Linehan, Michelle Smidak, Richard Houghton, Olufunmilayo Osiguwa et al. « Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins ». Journal of General Virology 90, no 3 (1 mars 2009) : 546–58. http://dx.doi.org/10.1099/vir.0.007930-0.
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Approximately 15 % of human prion disease is associated with autosomal-dominant pathogenic mutations in the prion protein (PrP) gene. Previous attempts to model these diseases in mice have expressed human PrP mutations in murine PrP, but this may have different structural consequences. Here, we describe transgenic mice expressing human PrP with P102L or E200K mutations and methionine (M) at the polymorphic residue 129. Although no spontaneous disease developed in aged animals, these mice were readily susceptible to prion infection from patients with the homotypic pathogenic mutation. However, while variant Creutzfeldt–Jakob disease (CJD) prions transmitted infection efficiently to both lines of mice, markedly different susceptibilities to classical (sporadic and iatrogenic) CJD prions were observed. Prions from E200K and classical CJD M129 homozygous patients, transmitted disease with equivalent efficiencies and short incubation periods in human PrP 200K, 129M transgenic mice. However, mismatch at residue 129 between inoculum and host dramatically increased the incubation period. In human PrP 102L, 129M transgenic mice, short disease incubation periods were only observed with transmissions of prions from P102L patients, whereas classical CJD prions showed prolonged and variable incubation periods irrespective of the codon 129 genotype. Analysis of disease-related PrP (PrPSc) showed marked alteration in the PrPSc glycoform ratio propagated after transmission of classical CJD prions, consistent with the PrP point mutations directly influencing PrPSc assembly. These data indicate that P102L or E200K mutations of human PrP have differing effects on prion propagation that depend upon prion strain type and can be significantly influenced by mismatch at the polymorphic residue 129.
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Tuite, Mick, Klement Stojanovski, Frederique Ness, Gloria Merritt et Nadejda Koloteva-Levine. « Cellular factors important for the de novo formation of yeast prions ». Biochemical Society Transactions 36, no 5 (19 septembre 2008) : 1083–87. http://dx.doi.org/10.1042/bst0361083.
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Prions represent an unusual structural form of a protein that is ‘infectious’. In mammals, prions are associated with fatal neurodegenerative diseases such as CJD (Creutzfeldt–Jakob disease), while in fungi they act as novel epigenetic regulators of phenotype. Even though most of the human prion diseases arise spontaneously, we still know remarkably little about how infectious prions form de novo. The [PSI+] prion of the yeast Saccharomyces cerevisiae provides a highly tractable model in which to explore the underlying mechanism of de novo prion formation, in particular identifying key cis- and trans-acting factors. Most significantly, the de novo formation of [PSI+] requires the presence of a second prion called [PIN+], which is typically the prion form of Rnq1p, a protein rich in glutamine and aspartic acid residues. The molecular mechanism by which the [PIN+] prion facilitates de novo [PSI+] formation is not fully established, but most probably involves some form of cross-seeding. A number of other cellular factors, in particular chaperones of the Hsp70 (heat-shock protein 70) family, are known to modify the frequency of de novo prion formation in yeast.
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Acquatella-Tran Van Ba, Isabelle, Thibaut Imberdis et Véronique Perrier. « From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases ». International Journal of Cell Biology 2013 (2013) : 1–8. http://dx.doi.org/10.1155/2013/975832.
Texte intégralRésumé :
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.
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Kushnirov, Vitaly V., Alexander A. Dergalev, Maya K. Alieva et Alexander I. Alexandrov. « Structural Bases of Prion Variation in Yeast ». International Journal of Molecular Sciences 23, no 10 (20 mai 2022) : 5738. http://dx.doi.org/10.3390/ijms23105738.
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Amyloids are protein aggregates with a specific filamentous structure that are related to a number of human diseases, and also to some important physiological processes in animals and other kingdoms of life. Amyloids in yeast can stably propagate as heritable units, prions. Yeast prions are of interest both on their own and as a model for amyloids and prions in general. In this review, we consider the structure of yeast prions and its variation, how such structures determine the balance of aggregated and soluble prion protein through interaction with chaperones and how the aggregated state affects the non-prion functions of these proteins.
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Siddiqi, Mohammad Khursheed, Chae Kim, Tracy Haldiman, Miroslava Kacirova, Benlian Wang, Jen Bohon, Mark R. Chance, Janna Kiselar et Jiri G. Safar. « Structurally distinct external solvent-exposed domains drive replication of major human prions ». PLOS Pathogens 17, no 6 (17 juin 2021) : e1009642. http://dx.doi.org/10.1371/journal.ppat.1009642.
Texte intégralRésumé :
There is a limited understanding of structural attributes that encode the iatrogenic transmissibility and various phenotypes of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Here we report the detailed structural differences between major sCJD MM1, MM2, and VV2 prions determined with two complementary synchrotron hydroxyl radical footprinting techniques—mass spectrometry (MS) and conformation dependent immunoassay (CDI) with a panel of Europium-labeled antibodies. Both approaches clearly demonstrate that the phenotypically distant prions differ in a major way with regard to their structural organization, and synchrotron-generated hydroxyl radicals progressively inhibit their seeding potency in a strain and structure-specific manner. Moreover, the seeding rate of sCJD prions is primarily determined by strain-specific structural organization of solvent-exposed external domains of human prion particles that control the seeding activity. Structural characteristics of human prion strains suggest that subtle changes in the organization of surface domains play a critical role as a determinant of human prion infectivity, propagation rate, and targeting of specific brain structures.
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Uchiyama, Keiji, Hironori Miyata, Yoshitaka Yamaguchi, Morikazu Imamura, Mariya Okazaki, Agriani Dini Pasiana, Junji Chida et al. « Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106 ». International Journal of Molecular Sciences 21, no 19 (1 octobre 2020) : 7260. http://dx.doi.org/10.3390/ijms21197260.
Texte intégralRésumé :
Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.
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Race, Brent, Katie Phillips, Kimberly Meade-White, James Striebel et Bruce Chesebro. « Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice Overexpressing Human Prion Protein ». Journal of Virology 89, no 11 (25 mars 2015) : 6022–32. http://dx.doi.org/10.1128/jvi.00362-15.
Texte intégralRésumé :
ABSTRACTPrion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previousin vivostudies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8- to 16-fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2- to 4-fold above normal.IMPORTANCEPrion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by mice expressing only anchorless PrP were more infectious than prions produced in mice expressing anchored PrP. Thus, the lack of the GPI anchor on prions reduced the effect of the mouse-human species barrier. Our results suggest that prion diseases that produce higher levels of anchorless PrP may pose an increased risk for cross-species infection.
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Avar, Merve, Daniel Heinzer, Nicolas Steinke, Berre Doğançay, Rita Moos, Severine Lugan, Claudia Cosenza, Simone Hornemann, Olivier Andréoletti et Adriano Aguzzi. « Prion infection, transmission, and cytopathology modeled in a low-biohazard human cell line ». Life Science Alliance 3, no 8 (30 juin 2020) : e202000814. http://dx.doi.org/10.26508/lsa.202000814.
Texte intégralRésumé :
Transmission of prion infectivity to susceptible murine cell lines has simplified prion titration assays and has greatly reduced the need for animal experimentation. However, murine cell models suffer from technical and biological constraints. Human cell lines might be more useful, but they are much more biohazardous and are often poorly infectible. Here, we describe the human clonal cell line hovS, which lacks the human PRNP gene and expresses instead the ovine PRNP VRQ allele. HovS cells were highly susceptible to the PG127 strain of sheep-derived murine prions, reaching up to 90% infected cells in any given culture and were maintained in a continuous infected state for at least 14 passages. Infected hovS cells produced proteinase K–resistant prion protein (PrPSc), pelletable PrP aggregates, and bona fide infectious prions capable of infecting further generations of naïve hovS cells and mice expressing the VRQ allelic variant of ovine PrPC. Infection in hovS led to prominent cytopathic vacuolation akin to the spongiform changes observed in individuals suffering from prion diseases. In addition to expanding the toolbox for prion research to human experimental genetics, the hovS cell line provides a human-derived system that does not require human prions. Hence, the manipulation of scrapie-infected hovS cells may present fewer biosafety hazards than that of genuine human prions.
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Sakudo, Akikazu, Risa Yamashiro et Chihiro Harata. « Effect of Non-Concentrated and Concentrated Vaporized Hydrogen Peroxide on Scrapie Prions ». Pathogens 9, no 11 (13 novembre 2020) : 947. http://dx.doi.org/10.3390/pathogens9110947.
Texte intégralRésumé :
To date, there have been no studies on the sterilization of prions by non-concentrated and concentrated vaporized hydrogen peroxide (VHP) applied by the same instrument. Here, the effect of the two types of VHP applied using an ES-700 sterilizer on prions was investigated. Brain homogenate from scrapie (Chandler) prion-infected mice was spotted on a cover glass and subjected to ES-700 treatment in soft (non-concentrated VHP from 59% hydrogen peroxide) or standard (concentrated VHP from 80% hydrogen peroxide) mode. Proteinase K-resistant prion protein (PrPres), an indicator of the abnormal isoform of prion protein (PrPSc), was reduced by ES-700 treatment under several conditions: SFT1/4 (soft mode, quarter cycle), SFT1/2 (soft mode, half cycle), SFT1 (soft mode, full cycle), and STD1/2 (standard mode, half cycle). PrPres was detected after the first and second rounds of protein misfolding cyclic amplification (PMCA) of untreated samples, but was undetectable in SFT1/4, SFT1/2, SFT1, and STD1/2 treated samples. In a mouse bioassay, SFT1/2 and STD1/2 treatment of prions significantly prolonged survival time, suggesting that prion infectivity is reduced after ES-700 treatment. In summary, both non-concentrated and concentrated VHP inactivate prions and may be useful for the low-temperature sterilization of prion-contaminated medical devices.
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Kobayashi, Atsushi, Nobuyuki Sakuma, Yuichi Matsuura, Shirou Mohri, Adriano Aguzzi et Tetsuyuki Kitamoto. « Experimental Verification of a Traceback Phenomenon in Prion Infection ». Journal of Virology 84, no 7 (20 janvier 2010) : 3230–38. http://dx.doi.org/10.1128/jvi.02387-09.
Texte intégralRésumé :
ABSTRACT The clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD) correlate with the allelotypes (M or V) of the polymorphic codon 129 of the human prion protein (PrP) gene and the electrophoretic mobility patterns of abnormal prion protein (PrPSc). Transmission of sCJD prions to mice expressing human PrP with a heterologous genotype (referred to as cross-sequence transmission) results in prolonged incubation periods. We previously reported that cross-sequence transmission can generate a new prion strain with unique transmissibility, designated a traceback phenomenon. To verify experimentally the traceback of sCJD-VV2 prions, we inoculated sCJD-VV2 prions into mice expressing human PrP with the 129M/M genotype. These 129M/M mice showed altered neuropathology and a novel PrPSc type after a long incubation period. We then passaged the brain homogenate from the 129M/M mouse inoculated with sCJD-VV2 prions into other 129M/M or 129V/V mice. Despite cross-sequence transmission, 129V/V mice were highly susceptible to these prions compared to the 129M/M mice. The neuropathology and PrPSc type of the 129V/V mice inoculated with the 129M/M mouse-passaged sCJD-VV2 prions were identical to those of the 129V/V mice inoculated with sCJD-VV2 prions. Moreover, we generated for the first time a type 2 PrPSc-specific antibody in addition to type 1 PrPSc-specific antibody and discovered that drastic changes in the PrPSc subpopulation underlie the traceback phenomenon. Here, we report the first direct evidence of the traceback in prion infection.
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Fleming, Eleanor, Andy H. Yuan, Danielle M. Heller et Ann Hochschild. « A bacteria-based genetic assay detects prion formation ». Proceedings of the National Academy of Sciences 116, no 10 (19 février 2019) : 4605–10. http://dx.doi.org/10.1073/pnas.1817711116.
Texte intégralRésumé :
Prions are infectious, self-propagating protein aggregates that are notorious for causing devastating neurodegenerative diseases in mammals. Recent evidence supports the existence of prions in bacteria. However, the evaluation of candidate bacterial prion-forming proteins has been hampered by the lack of genetic assays for detecting their conversion to an aggregated prion conformation. Here we describe a bacteria-based genetic assay that distinguishes cells carrying a model yeast prion protein in its nonprion and prion forms. We then use this assay to investigate the prion-forming potential of single-stranded DNA-binding protein (SSB) ofCampylobacter hominis. Our findings indicate that SSB possesses a prion-forming domain that can transition between nonprion and prion conformations. Furthermore, we show that bacterial cells can propagate the prion form over 100 generations in a manner that depends on the disaggregase ClpB. The bacteria-based genetic tool we present may facilitate the investigation of prion-like phenomena in all domains of life.
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Munoz-Montesino, Carola, Djabir Larkem, Clément Barbereau, Angélique Igel-Egalon, Sandrine Truchet, Eric Jacquet, Naïma Nhiri et al. « A seven-residue deletion in PrP leads to generation of a spontaneous prion formed from C-terminal C1 fragment of PrP ». Journal of Biological Chemistry 295, no 41 (11 août 2020) : 14025–39. http://dx.doi.org/10.1074/jbc.ra120.014738.
Texte intégralRésumé :
Prions result from a drastic conformational change of the host-encoded cellular prion protein (PrP), leading to the formation of β-sheet–rich, insoluble, and protease-resistant self-replicating assemblies (PrPSc). The cellular and molecular mechanisms involved in spontaneous prion formation in sporadic and inherited human prion diseases or equivalent animal diseases are poorly understood, in part because cell models of spontaneously forming prions are currently lacking. Here, extending studies on the role of the H2 α-helix C terminus of PrP, we found that deletion of the highly conserved 190HTVTTTT196 segment of ovine PrP led to spontaneous prion formation in the RK13 rabbit kidney cell model. On long-term passage, the mutant cells stably produced proteinase K (PK)–resistant, insoluble, and aggregated assemblies that were infectious for naïve cells expressing either the mutant protein or other PrPs with slightly different deletions in the same area. The electrophoretic pattern of the PK-resistant core of the spontaneous prion (ΔSpont) contained mainly C-terminal polypeptides akin to C1, the cell-surface anchored C-terminal moiety of PrP generated by natural cellular processing. RK13 cells expressing solely the Δ190–196 C1 PrP construct, in the absence of the full-length protein, were susceptible to ΔSpont prions. ΔSpont infection induced the conversion of the mutated C1 into a PK-resistant and infectious form perpetuating the biochemical characteristics of ΔSpont prion. In conclusion, this work provides a unique cell-derived system generating spontaneous prions and provides evidence that the 113 C-terminal residues of PrP are sufficient for a self-propagating prion entity.
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Sakudo, Akikazu, Yoshifumi Iwamaru, Koichi Furusaki, Makoto Haritani, Rumiko Onishi, Morikazu Imamura, Takashi Yokoyama, Yasuhiro Yoshikawa et Takashi Onodera. « Inactivation of Scrapie Prions by the Electrically Charged Disinfectant CAC-717 ». Pathogens 9, no 7 (3 juillet 2020) : 536. http://dx.doi.org/10.3390/pathogens9070536.
Texte intégralRésumé :
Previous studies have revealed that the electrically charged disinfectant CAC-717 has strong virucidal and bactericidal effects but is safe for humans and animals. In this study, CAC-717 was further evaluated for its potential effects as a disinfectant against scrapie prions. Western blotting showed that CAC-717 reduced the amount of the abnormal isoform of prion protein (PrPSc) in prion-infected cell (ScN2a) lysates. Furthermore, the reduction of prion transmissibility was confirmed by a mouse bioassay, in which mice injected with scrapie prions pre-treated with CAC-717 survived longer than those injected with untreated scrapie prions. Lastly, to evaluate the seeding activity of ScN2a cell lysates treated with CAC-717, quantitative protein misfolding cyclic amplification (PMCA) was performed directly on ScN2a cell lysates treated with CAC-717, which showed that the median dose of PMCA (PMCA50) dropped from log9.95 to log5.20 after CAC-717 treatment, indicating more than a 4 log reduction. This suggests that the seeding activity of PrPSc is decreased by CAC-717. Collectively, these results suggest that CAC-717 has anti-prion activity, reducing both PrPSc conversion activity and prion transmissibility; thus, CAC-717 will be useful as a novel disinfectant in prion diseases.
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Hara, Hideyuki, Junji Chida, Agriani Dini Pasiana, Keiji Uchiyama, Yutaka Kikuchi, Tomoko Naito, Yuichi Takahashi, Junji Yamamura, Hisashi Kuromatsu et Suehiro Sakaguchi. « Vaporized Hydrogen Peroxide and Ozone Gas Synergistically Reduce Prion Infectivity on Stainless Steel Wire ». International Journal of Molecular Sciences 22, no 6 (23 mars 2021) : 3268. http://dx.doi.org/10.3390/ijms22063268.
Texte intégralRésumé :
Prions are infectious agents causing prion diseases, which include Creutzfeldt–Jakob disease (CJD) in humans. Several cases have been reported to be transmitted through medical instruments that were used for preclinical CJD patients, raising public health concerns on iatrogenic transmissions of the disease. Since preclinical CJD patients are currently difficult to identify, medical instruments need to be adequately sterilized so as not to transmit the disease. In this study, we investigated the sterilizing activity of two oxidizing agents, ozone gas and vaporized hydrogen peroxide, against prions fixed on stainless steel wires using a mouse bioassay. Mice intracerebrally implanted with prion-contaminated stainless steel wires treated with ozone gas or vaporized hydrogen peroxide developed prion disease later than those implanted with control prion-contaminated stainless steel wires, indicating that ozone gas and vaporized hydrogen peroxide could reduce prion infectivity on wires. Incubation times were further elongated in mice implanted with prion-contaminated stainless steel wires treated with ozone gas-mixed vaporized hydrogen peroxide, indicating that ozone gas mixed with vaporized hydrogen peroxide reduces prions on these wires more potently than ozone gas or vaporized hydrogen peroxide. These results suggest that ozone gas mixed with vaporized hydrogen peroxide might be more useful for prion sterilization than ozone gas or vaporized hydrogen peroxide alone.
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Ma, Jiyan, Jingjing Zhang et Runchuan Yan. « Recombinant Mammalian Prions : The “Correctly” Misfolded Prion Protein Conformers ». Viruses 14, no 9 (31 août 2022) : 1940. http://dx.doi.org/10.3390/v14091940.
Texte intégralRésumé :
Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of misfolded recPrP conformers have been generated, but despite their seeding capability, many of them have failed to elicit a fatal neurodegenerative disorder in wild-type animals like a naturally occurring prion. The application of the protein misfolding cyclic amplification technique and the inclusion of non-protein cofactors in the reaction mixture have led to the generation of authentic recombinant prions that fully recapitulate the characteristics of native prions. Together, these studies reveal that recPrP can stably exist in a variety of misfolded conformations and when inoculated into wild-type animals, misfolded recPrP conformers cause a wide range of outcomes, from being completely innocuous to lethal. Since all these recPrP conformers possess seeding capabilities, these results clearly suggest that seeding activity alone is not equivalent to prion activity. Instead, authentic prions are those PrP conformers that are not only heritable (the ability to seed the conversion of normal PrP) but also pathogenic (the ability to cause fatal neurodegeneration). The knowledge gained from the studies of the recombinant prion is important for us to understand the pathogenesis of prion disease and the roles of misfolded proteins in other neurodegenerative disorders.
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Sakudo, Akikazu, et Yosuke Tsuji. « Hydrogen Peroxide Gas Plasma Sterilizer Combined with Dielectric Barrier Discharge and Corona Discharge Inactivates Prions ». Applied Sciences 11, no 20 (19 octobre 2021) : 9777. http://dx.doi.org/10.3390/app11209777.
Texte intégralRésumé :
Prions are highly resistant to physical or chemical damage, although previous studies have shown that STERRAD®, a hydrogen gas plasma sterilizer using radiofrequency (RF) discharge, has an inactivation effect. Here, the effect of hydrogen peroxide gas combined with dielectric barrier discharge (DBD) plasma and corona discharge plasma using a RENO-S130 sterilizer on scrapie prions was examined. Scrapie prion-infected mouse brain homogenate was air-dried on a cover glass, sealed in a Tyvek pouch, and subjected to RENO-S130 treatment using either non-lumen mode (28 min) or Eco mode (45 min) with hydrogen peroxide gas derived from 50% hydrogen peroxide. Control (untreated) samples were prepared on a cover glass using the same procedure but without exposure to RENO-S130. PrPres (proteinase K (PK)-resistant prion protein), an index of the conformational variant of prion protein (PrPSc), was decreased by treatment with RENO-S130 under both modes of operation. Specifically, PrPres was identified after the 1st and 2nd cycles of protein misfolding cyclic amplification (PMCA) in control samples but was below the detection limit in RENO-S130-treated samples. A bioassay showed that treatment of prions with RENO-S130 (non-lumen or Eco mode) significantly prolonged mouse survival time. Taken together, these findings show hydrogen peroxide gas combined with DBD/corona discharge plasma can inactivate prions by reducing prion propagation and prion infectivity. This treatment is potentially applicable to the sterilization of prion-contaminated heat-sensitive medical devices.
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Wadsworth, Jonathan D. F., Susan Joiner, Jacqueline M. Linehan, Emmanuel A. Asante, Sebastian Brandner et John Collinge. « The origin of the prion agent of kuru : molecular and biological strain typing ». Philosophical Transactions of the Royal Society B : Biological Sciences 363, no 1510 (27 novembre 2008) : 3747–53. http://dx.doi.org/10.1098/rstb.2008.0069.
Texte intégralRésumé :
Kuru is an acquired human prion disease that primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. The central clinical feature of kuru is progressive cerebellar ataxia and, in sharp contrast to most cases of sporadic Creutzfeldt–Jakob disease (CJD), dementia is a less prominent and usually late clinical feature. In this regard, kuru is more similar to variant CJD, which also has similar prodromal symptoms of sensory disturbance and joint pains in the legs and psychiatric and behavioural changes. Since a significant part of the clinicopathological diversity seen in human prion disease is likely to relate to the propagation of distinct human prion strains, we have compared the transmission properties of kuru prions with those isolated from patients with sporadic, iatrogenic and variant CJD in both transgenic and wild-type mice. These data have established that kuru prions have prion strain properties equivalent to those of classical (sporadic and iatrogenic) CJD prions but distinct from variant CJD prions. Here, we review these findings and discuss how peripheral routes of infection and other factors may be critical modifiers of the kuru phenotype.
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Killian, Andrea N., Sarah C. Miller et Justin K. Hines. « Impact of Amyloid Polymorphism on Prion-Chaperone Interactions in Yeast ». Viruses 11, no 4 (16 avril 2019) : 349. http://dx.doi.org/10.3390/v11040349.
Texte intégralRésumé :
Yeast prions are protein-based genetic elements found in the baker’s yeast Saccharomyces cerevisiae, most of which are amyloid aggregates that propagate by fragmentation and spreading of small, self-templating pieces called propagons. Fragmentation is carried out by molecular chaperones, specifically Hsp104, Hsp70, and Hsp40. Like other amyloid-forming proteins, amyloid-based yeast prions exhibit structural polymorphisms, termed “strains” in mammalian systems and “variants” in yeast, which demonstrate diverse phenotypes and chaperone requirements for propagation. Here, the known differential interactions between chaperone proteins and yeast prion variants are reviewed, specifically those of the yeast prions [PSI+], [RNQ+]/[PIN+], and [URE3]. For these prions, differences in variant-chaperone interactions (where known) with Hsp104, Hsp70s, Hsp40s, Sse1, and Hsp90 are summarized, as well as some interactions with chaperones of other species expressed in yeast. As amyloid structural differences greatly impact chaperone interactions, understanding and accounting for these variations may be crucial to the study of chaperones and both prion and non-prion amyloids.
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Ayers, Jacob I., Nick A. Paras et Stanley B. Prusiner. « Expanding spectrum of prion diseases ». Emerging Topics in Life Sciences 4, no 2 (17 août 2020) : 155–67. http://dx.doi.org/10.1042/etls20200037.
Texte intégralRésumé :
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.
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Bian, Jifeng, Dana Napier, Vadim Khaychuck, Rachel Angers, Catherine Graham et Glenn Telling. « Cell-Based Quantification of Chronic Wasting Disease Prions ». Journal of Virology 84, no 16 (2 juin 2010) : 8322–26. http://dx.doi.org/10.1128/jvi.00633-10.
Texte intégralRésumé :
ABSTRACT Cell-based measurement of prion infectivity is currently restricted to experimental strains of mouse-adapted scrapie. Having isolated cell cultures with susceptibility to prions from diseased elk, we describe a modification of the scrapie cell assay allowing evaluation of prions causing chronic wasting disease, a naturally occurring transmissible spongiform encephalopathy. We compare this cervid prion cell assay to bioassays in transgenic mice, the only other existing method for quantification, and show this assay to be a relatively economical and expedient alternative that will likely facilitate studies of this important prion disease.