Journal articles: 'Prions'

1

Bostock, Chris. "Prions prions prions." Virus Research 48, no. 1 (April 1997): 107–8. http://dx.doi.org/10.1016/s0168-1702(96)01414-1.

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2

Livingston, K. "More on Prions: Prions Prions Prions." Science 273, no. 5278 (August 23, 1996): 1053a. http://dx.doi.org/10.1126/science.273.5278.1053a.

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3

Obi, R. K., and F. C. Nwanebu. "Prions And Prion Diseases." African Journal of Clinical and Experimental Microbiology 9, no. 1 (January 14, 2008): 38. http://dx.doi.org/10.4314/ajcem.v9i1.7481.

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4

Beekes, Michael. "Prions and prion diseases." FEBS Journal 274, no. 3 (January 8, 2007): 575. http://dx.doi.org/10.1111/j.1742-4658.2006.05629.x.

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5

Wickner, R. B., K. L. Taylor, H. K. Edskes, and M.-L. Maddelein. "Prions: Portable prion domains." Current Biology 10, no. 9 (May 2000): R335—R337. http://dx.doi.org/10.1016/s0960-9822(00)00460-7.

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6

Nixon, Randal R. "Prions and Prion Diseases." Laboratory Medicine 30, no. 5 (May 1, 1999): 335–38. http://dx.doi.org/10.1093/labmed/30.5.335.

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7

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 (January 17, 2017): 1141–46. http://dx.doi.org/10.1073/pnas.1611891114.

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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.

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Watts, Joel C., Kurt Giles, Daniel J. Saltzberg, Brittany N. Dugger, Smita Patel, Abby Oehler, Sumita Bhardwaj, Andrej Sali, and 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 (July 20, 2016): 9558–69. http://dx.doi.org/10.1128/jvi.01106-16.

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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.

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9

Gambetti, P. "Approaches to Prions: Prion Diseases." Science 273, no. 5278 (August 23, 1996): 1052b—1053b. http://dx.doi.org/10.1126/science.273.5278.1052b.

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10

Stahl, Neil, and Stanley B. Prusiner. "Prions and prion proteins 1." FASEB Journal 5, no. 13 (October 1991): 2799–807. http://dx.doi.org/10.1096/fasebj.5.13.1916104.

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11

Fraser, Paul E. "Prions and Prion-like Proteins." Journal of Biological Chemistry 289, no. 29 (May 23, 2014): 19839–40. http://dx.doi.org/10.1074/jbc.r114.583492.

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12

Fisher, Elizabeth, Glenn Telling, and John Collinge. "Prions and the prion disorders." Mammalian Genome 9, no. 7 (July 1, 1998): 497–502. http://dx.doi.org/10.1007/s003359900807.

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13

Jones, Rachel. "Prions, prions everywhere." Nature Reviews Neuroscience 4, no. 1 (January 2003): 11. http://dx.doi.org/10.1038/nrn1020.

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14

Miller, Sarah C., Andrea K. Wegrzynowicz, Sierra J. Cole, Rachel E. Hayward, Samantha J. Ganser, and Justin K. Hines. "Hsp40/JDP Requirements for the Propagation of Synthetic Yeast Prions." Viruses 14, no. 10 (September 30, 2022): 2160. http://dx.doi.org/10.3390/v14102160.

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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.

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15

Krauss, Sybille, and 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.

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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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16

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 (January 1, 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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17

Bodemer, Walter. "Prions." Primate Biology 3, no. 2 (September 7, 2016): 47–50. http://dx.doi.org/10.5194/pb-3-47-2016.

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Abstract. Prions gained widespread public and scientific interest in the year 2000. At that time, the human neurological Creutzfeldt–Jakob disease (CJD) was known. However, new CJD cases were diagnosed but they could not be ascribed to one of the classical CJD categories i.e. sporadic (sCJD), hereditary or acquired. Hence, they were classified as variant CJD (vCJD). Later on, experimental evidence suggested that vCJD was caused by prions postulated as unique novel infectious agents and, for example, responsible for bovine spongiform encephalopathy (BSE) also known as mad cow disease. The infection of humans by transmission of BSE prions also defined vCJD as a zoonotic disease. Prions, especially those associated with scrapie in sheep had been known for quite some time and misleadingly discussed as a slow virus. Therefore, this enigmatic pathogen and the transmission of this unusual infectious agent was a matter of a controversial scientific debate. An agent without nucleic acid did not follow the current dogma postulating DNA or RNA as inheritable information encoding molecules. Although numerous experimental results clearly demonstrated the infectious capacity of prions in several animal species, a model close to human was not readily available. Therefore, the use of rhesus monkeys (Macaca mulatta) served as a non-human primate model to elucidate prion infection under controlled experimental conditions. Not the least, transmission of BSE, human vCJD, and sCJD prions could be confirmed in our study. Any prion infection concomitant with progression of disease in humans, especially vCJD, could be analyzed only retrospectively and at late stages of disease. In contrast, the prion-infected rhesus monkeys were accessible before and after infection; the progression from early stage to late clinical stages – and eventually death of the animal – could be traced. Because of the phylogenetic proximity to humans, the rhesus monkey was superior to any rodent or other animal model. For these reasons an experimental approach had been conceived by J. Collinge in London and A. Aguzzi in Zurich and performed in a cooperative study with both research groups in the pathology unit of the German Primate Center (DPZ). The study in the DPZ lasted from 2001 until 2012. Our research in the pathology unit provided a temporal monitoring of how an initial prion infection develops eventually into disease; an approach that would have never been possible in humans since the time point of infection with prions from, for example, BSE is always unknown. Telemetry revealed a shift in sleep–wake cycles early on, long before behavioral changes or clinical symptoms appeared. Pathology confirmed non-neuronal tissue as hidden places where prions exist. The rhesus model also allowed first comparative studies of epigenetic modifications on RNA in peripheral blood and brain tissue collected from uninfected and prion-infected animals. To conclude, our studies clearly demonstrated that this model is valid since progression to disease is almost identical to human CJD.

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18

Krejciova, Zuzana, James Alibhai, Chen Zhao, Robert Krencik, Nina M. Rzechorzek, Erik M. Ullian, Jean Manson, James W. Ironside, Mark W. Head, and Siddharthan Chandran. "Human stem cell–derived astrocytes replicate human prions in a PRNP genotype–dependent manner." Journal of Experimental Medicine 214, no. 12 (November 15, 2017): 3481–95. http://dx.doi.org/10.1084/jem.20161547.

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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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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 (October 1, 2020): 7260. http://dx.doi.org/10.3390/ijms21197260.

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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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20

Safar, Jiri G., Klaus Kellings, Ana Serban, Darlene Groth, James E. Cleaver, Stanley B. Prusiner, and Detlev Riesner. "Search for a Prion-Specific Nucleic Acid." Journal of Virology 79, no. 16 (August 15, 2005): 10796–806. http://dx.doi.org/10.1128/jvi.79.16.10796-10806.2005.

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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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21

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 (August 18, 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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Son, Moonil, and Reed B. Wickner. "Anti-Prion Systems in Saccharomyces cerevisiae Turn an Avalanche of Prions into a Flurry." Viruses 14, no. 9 (September 1, 2022): 1945. http://dx.doi.org/10.3390/v14091945.

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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.

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Evarts, Jacob, and 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.

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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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Jheeta, Sohan, Elias Chatzitheodoridis, Kevin Devine, and Janice Block. "The Way forward for the Origin of Life: Prions and Prion-Like Molecules First Hypothesis." Life 11, no. 9 (August 25, 2021): 872. http://dx.doi.org/10.3390/life11090872.

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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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Mathiason, Candace K. "Silent Prions and Covert Prion Transmission." PLOS Pathogens 11, no. 12 (December 10, 2015): e1005249. http://dx.doi.org/10.1371/journal.ppat.1005249.

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26

Ridler, Charlotte. "'Anti-prions' block prion disease onset." Nature Reviews Neurology 13, no. 9 (July 7, 2017): 514. http://dx.doi.org/10.1038/nrneurol.2017.100.

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Gilch, Sabine, and Hermann M. Schätzl. "Aptamers against prion proteins and prions." Cellular and Molecular Life Sciences 66, no. 15 (April 25, 2009): 2445–55. http://dx.doi.org/10.1007/s00018-009-0031-5.

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28

Belay, Ermias D. "Prions and Prion Diseases: Current Perspectives." Emerging Infectious Diseases 10, no. 12 (December 2004): 2265–66. http://dx.doi.org/10.3201/eid1012.3040847.

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29

Malato, Laurent, and Sven J. Saupe. "Fungal prions: When proteins turn into genes." Biochemist 27, no. 4 (August 1, 2005): 14–18. http://dx.doi.org/10.1042/bio02704014.

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Prions are infectious proteic particles devoid of nucleic acids that can cause devastating neurological disorders in mammals. Prions have also been identified in simpler organisms, namely unicellular yeasts and filamentous fungi. These fungal prions represent valuable model systems because they are safe to handle and, compared with mammalian prions, easier to study. In this article, we summarize the basic characteristics of the fungal prions and attempt to describe how their discovery has affected and expanded the prion concept.

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Kushnirov, Vitaly V., Alexander A. Dergalev, Maya K. Alieva, and Alexander I. Alexandrov. "Structural Bases of Prion Variation in Yeast." International Journal of Molecular Sciences 23, no. 10 (May 20, 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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Wälzlein, Joo-Hee, Karla A. Schwenke, and Michael Beekes. "Propagation of CJD Prions in Primary Murine Glia Cells Expressing Human PrPc." Pathogens 10, no. 8 (August 20, 2021): 1060. http://dx.doi.org/10.3390/pathogens10081060.

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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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Barbitoff, Yury A., Andrew G. Matveenko, and Galina A. Zhouravleva. "Differential Interactions of Molecular Chaperones and Yeast Prions." Journal of Fungi 8, no. 2 (January 27, 2022): 122. http://dx.doi.org/10.3390/jof8020122.

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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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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 (May 2016): 160035. http://dx.doi.org/10.1098/rsob.160035.

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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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Kobayashi, Atsushi, Nobuyuki Sakuma, Yuichi Matsuura, Shirou Mohri, Adriano Aguzzi, and Tetsuyuki Kitamoto. "Experimental Verification of a Traceback Phenomenon in Prion Infection." Journal of Virology 84, no. 7 (January 20, 2010): 3230–38. http://dx.doi.org/10.1128/jvi.02387-09.

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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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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 (September 8, 2020): 23815–22. http://dx.doi.org/10.1073/pnas.2007406117.

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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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Schmidt, Christian, Jeremie Fizet, Francesca Properzi, Mark Batchelor, Malin K. Sandberg, Julie A. Edgeworth, Louise Afran, et al. "A systematic investigation of production of synthetic prions from recombinant prion protein." Open Biology 5, no. 12 (December 2015): 150165. http://dx.doi.org/10.1098/rsob.150165.

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According to the protein-only hypothesis, infectious mammalian prions, which exist as distinct strains with discrete biological properties, consist of multichain assemblies of misfolded cellular prion protein (PrP). A critical test would be to produce prion strains synthetically from defined components. Crucially, high-titre ‘synthetic' prions could then be used to determine the structural basis of infectivity and strain diversity at the atomic level. While there have been multiple reports of production of prions from bacterially expressed recombinant PrP using various methods, systematic production of high-titre material in a form suitable for structural analysis remains a key goal. Here, we report a novel high-throughput strategy for exploring a matrix of conditions, additives and potential cofactors that might generate high-titre prions from recombinant mouse PrP, with screening for infectivity using a sensitive automated cell-based bioassay. Overall, approximately 20 000 unique conditions were examined. While some resulted in apparently infected cell cultures, this was transient and not reproducible. We also adapted published methods that reported production of synthetic prions from recombinant hamster PrP, but again did not find evidence of significant infectious titre when using recombinant mouse PrP as substrate. Collectively, our findings are consistent with the formation of prion infectivity from recombinant mouse PrP being a rare stochastic event and we conclude that systematic generation of prions from recombinant PrP may only become possible once the detailed structure of authentic ex vivo prions is solved.

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Block, Alyssa J., Ronald A. Shikiya, Thomas E. Eckland, Anthony E. Kincaid, Ryan W. Walters, Jiyan Ma, and Jason C. Bartz. "Efficient interspecies transmission of synthetic prions." PLOS Pathogens 17, no. 7 (July 14, 2021): e1009765. http://dx.doi.org/10.1371/journal.ppat.1009765.

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Prions are comprised solely of PrPSc, the misfolded self-propagating conformation of the cellular protein, PrPC. Synthetic prions are generated in vitro from minimal components and cause bona fide prion disease in animals. It is unknown, however, if synthetic prions can cross the species barrier following interspecies transmission. To investigate this, we inoculated Syrian hamsters with murine synthetic prions. We found that all the animals inoculated with murine synthetic prions developed prion disease characterized by a striking uniformity of clinical onset and signs of disease. Serial intraspecies transmission resulted in a rapid adaptation to hamsters. During the adaptation process, PrPSc electrophoretic migration, glycoform ratios, conformational stability and biological activity as measured by protein misfolding cyclic amplification remained constant. Interestingly, the strain that emerged shares a strikingly similar transmission history, incubation period, clinical course of disease, pathology and biochemical and biological features of PrPSc with 139H, a hamster adapted form of the murine strain 139A. Combined, these data suggest that murine synthetic prions are comprised of bona fide PrPSc with 139A-like strain properties that efficiently crosses the species barrier and rapidly adapts to hamsters resulting in the emergence of a single strain. The efficiency and specificity of interspecies transmission of murine synthetic prions to hamsters, with relevance to brain derived prions, could be a useful model for identification of structure function relationships between PrPSc and PrPC from different species.

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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 (July 26, 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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Groener, Albrecht, Wolfram Schäfer, Henry Baron, and Martin Vey. "Hamster Prions Are a Suitable Model for Partitioning of Human CJD Prions during Plasma Processing Steps." Blood 104, no. 11 (November 16, 2004): 3644. http://dx.doi.org/10.1182/blood.v104.11.3644.3644.

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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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Tahir, Waqas, Basant Abdulrahman, Dalia H. Abdelaziz, Simrika Thapa, Rupali Walia, and Hermann M. Schätzl. "An astrocyte cell line that differentially propagates murine prions." Journal of Biological Chemistry 295, no. 33 (June 19, 2020): 11572–83. http://dx.doi.org/10.1074/jbc.ra120.012596.

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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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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 (March 1, 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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Mathur, Vidhu, Vibha Taneja, Yidi Sun, and 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 (May 2010): 1449–61. http://dx.doi.org/10.1091/mbc.e09-11-0927.

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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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Kang, Hae-Eun, Youngwon Mo, Raihah Abd Rahim, Hye-Mi Lee, and 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.

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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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Tamgüney, Gültekin, Michael W. Miller, Kurt Giles, Azucena Lemus, David V. Glidden, Stephen J. DeArmond, and Stanley B. Prusiner. "Transmission of scrapie and sheep-passaged bovine spongiform encephalopathy prions to transgenic mice expressing elk prion protein." Journal of General Virology 90, no. 4 (April 1, 2009): 1035–47. http://dx.doi.org/10.1099/vir.0.007500-0.

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Chronic wasting disease (CWD) is a transmissible, fatal prion disease of cervids and is largely confined to North America. The origin of CWD continues to pose a conundrum: does the disease arise spontaneously or result from some other naturally occurring reservoir? To address whether prions from sheep might be able to cause disease in cervids, we inoculated mice expressing the elk prion protein (PrP) transgene [Tg(ElkPrP) mice] with two scrapie prion isolates. The SSBP/1 scrapie isolate transmitted disease to Tg(ElkPrP) mice with a median incubation time of 270 days, but a second isolate failed to produce neurological dysfunction in these mice. Although prions from cattle with bovine spongiform encephalopathy (BSE) did not transmit to the Tg(ElkPrP) mice, they did transmit after being passaged through sheep. In Tg(ElkPrP) mice, the sheep-passaged BSE prions exhibited an incubation time of approximately 300 days. SSBP/1 prions produced abundant deposits of the disease-causing PrP isoform, denoted PrPSc, in the cerebellum and pons of Tg(ElkPrP) mice, whereas PrPSc accumulation in Tg mice inoculated with sheep-passaged BSE prions was confined to the deep cerebellar nuclei, habenula and the brainstem. The susceptibility of ‘cervidized’ mice to ‘ovinized’ prions raises the question about why CWD has not been reported in other parts of the world where cervids and scrapie-infected sheep coexist.

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Green, Kristi M., Shawn R. Browning, Tanya S. Seward, Jean E. Jewell, Dana L. Ross, Michael A. Green, Elizabeth S. Williams, Edward A. Hoover, and Glenn C. Telling. "The elk PRNP codon 132 polymorphism controls cervid and scrapie prion propagation." Journal of General Virology 89, no. 2 (February 1, 2008): 598–608. http://dx.doi.org/10.1099/vir.0.83168-0.

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The elk prion protein gene (PRNP) encodes either methionine (M) or leucine (L) at codon 132, the L132 allele apparently affording protection against chronic wasting disease (CWD). The corresponding human codon 129 polymorphism influences the host range of bovine spongiform encephalopathy (BSE) prions. To fully address the influence of this cervid polymorphism on CWD pathogenesis, we created transgenic (Tg) mice expressing cervid PrPC with L at residue 132, referred to as CerPrPC-L132, and compared the transmissibility of CWD prions from elk of defined PRNP genotypes, namely homozygous M/M or L/L or heterozygous M/L, in these Tg mice with previously described Tg mice expressing CerPrPC-M132, referred to as Tg(CerPrP) mice. While Tg(CerPrP) mice were consistently susceptible to CWD prions from elk of all three genotypes, Tg(CerPrP-L132) mice uniformly failed to develop disease following challenge with CWD prions. In contrast, SSBP/1 sheep scrapie prions transmitted efficiently to both Tg(CerPrP) and Tg(CerPrP-L132) mice. Our findings suggest that the elk 132 polymorphism controls prion susceptibility at the level of prion strain selection and that cervid PrP L132 severely restricts propagation of CWD prions. We speculate that the L132 polymorphism results in less efficient conversion of CerPrPC-L132 by CWD prions, an effect that is overcome by the SSBP/1 strain. Our studies show the accumulation of subclinical levels of CerPrPSc in aged asymptomatic CWD-inoculated Tg(CerPrP-L132) mice and also suggests the establishment of a latent infection state in apparently healthy elk expressing this seemingly protective allele.

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Böckmann, Anja, and Beat Meier. "Prions." Prion 4, no. 2 (April 2010): 72–79. http://dx.doi.org/10.4161/pri.4.2.11963.

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Godoy, J. M., M. Skacel, and D. H. Nicaretta. "Prions." Arquivos de Neuro-Psiquiatria 49, no. 2 (June 1991): 123–27. http://dx.doi.org/10.1590/s0004-282x1991000200001.

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Colby, D. W., and S. B. Prusiner. "Prions." Cold Spring Harbor Perspectives in Biology 3, no. 1 (January 1, 2011): a006833. http://dx.doi.org/10.1101/cshperspect.a006833.

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Shkundina, I. S., and M. D. Ter-Avanesyan. "Prions." Biochemistry (Moscow) 72, no. 13 (December 2007): 1519–36. http://dx.doi.org/10.1134/s0006297907130081.

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Rigler, Rudolf. "Prions." NeuroReport 8, no. 17 (December 1997): iii—v. http://dx.doi.org/10.1097/00001756-199712010-00038.

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Journal articles on the topic 'Prions'

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