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Rosa Bolea, Carlos Hedman, Óscar López-Pérez, Belén Marín, Enríc Vidal, Martí Pumarola, Fabien Corbière, Antonio Romero, Bernardino Moreno, Inmaculada Martín-Burriel, Olivier Andréoletti, Juan José Badiola
Multiple theories exist regarding the origin of bovine spongiform encephalopathy (BSE). An early and prominent theory proposed that BSE was the result of the adaptation of sheep scrapie to cattle. The reports to date indicate that the distribution of the pathological prion protein (PrPSc) in experimental bovine scrapie is largely restricted to the central nervous system (CNS). Here, we describe pathological findings in a calf intracerebrally inoculated with a Spanish classical scrapie isolate. While clinical disease was observed 30 months after inoculation and PrPSc was detected in the CNS, the corresponding phenotype differed from that of BSE...
September 18, 2017: Journal of General Virology
Bradley R Groveman, Gregory J Raymond, Katrina J Campbell, Brent Race, Lynne D Raymond, Andrew G Hughson, Christina D Orrú, Allison Kraus, Katie Phillips, Byron Caughey
Mammalian prion structures and replication mechanisms are poorly understood. Most synthetic recombinant prion protein (rPrP) amyloids prepared without cofactors are non-infectious or much less infectious than bona fide tissue-derived PrPSc. This effect has been associated with differences in folding of the aggregates, manifested in part by reduced solvent exclusion and protease-resistance in rPrP amyloids, especially within residues ~90-160. Substitution of 4 lysines within residues 101-110 of rPrP (central lysine cluster) with alanines (K4A) or asparagines (K4N) allows formation of aggregates with extended proteinase K (PK) resistant cores reminiscent of PrPSc, particularly when seeded with PrPSc...
September 14, 2017: PLoS Pathogens
Jelka Zabavnik, Marko Cotman, Polona Juntes, Ivan Ambrozic
Sheep with valine (V) at codon 136 and glutamine (Q) at codon 171 of the prion protein gene ( Prnp) are highly susceptible to classical scrapie, whereas phenylalanine (F) at codon 141 and histidine (H) at codon 154 play a major role in the susceptibility to atypical scrapie. A TaqMan real-time PCR assay was developed to determine Prnp alleles at codons 136, 141, 154, and 171 and used in classical scrapie eradication and breeding programs adopted in Slovenia. The frequency of the most resistant genotypes ARR/ARR and ARR/ARQ increased significantly in tested animals ( n = 35,138) from 6...
September 1, 2017: Journal of Veterinary Diagnostic Investigation
Penelope Papasavva-Stylianou, Marion Mathieson Simmons, Angel Ortiz-Pelaez, Otto Windl, John Spiropoulos, Soteria Georgiadou
This report presents the results of experimental challenges of goats with scrapie by both the intracerebral and oral routes, exploring the effects of polymorphisms at codon 146 of the goat PRNP gene on resistance to disease. The results of these studies illustrate that while goats of all genotypes can be infected by intracerebral (ic) challenge, the survival distribution of the animals homozygous for asparagine at codon 146 was significantly shorter than for all other genotypes (chi2 =10.8. P=0.001). In contrast, only those animals homozygous for asparagine at codon 146 (NN) succumb to oral challenge...
September 6, 2017: Journal of Virology
Natallia Makarava, Regina Savtchenko, Ilia V Baskakov
Protein misfolding cyclic amplification (PMCA) amplifies infectious prions in vitro. Over the past decade, PMCA has become an essential tool in prion research. The current chapter describes in detail the PMCA format with beads (PMCAb) and several methods that rely on PMCAb for assessing strain-specific prion amplification rates, for selective amplification of subtypes of PrP(Sc) from a mixture, and a PMCAb approach that can replace animal titration of scrapie material. Development of PMCAb-based methodology is important for addressing a number of research topics including prion strain evolution, selection and adaptation, strain-typing, prion detection, and biochemical requirements for prion replication...
2017: Methods in Molecular Biology
Suzana Aulić, Lara Masperone, Joanna Narkiewicz, Elisa Isopi, Edoardo Bistaffa, Elena Ambrosetti, Beatrice Pastore, Elena De Cecco, Denis Scaini, Paola Zago, Fabio Moda, Fabrizio Tagliavini, Giuseppe Legname
The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrP(C)) in mediating the uptake and the spread of recombinant α-Syn amyloids. The in vitro data revealed that the presence of PrP(C) fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed in vivo in wild type (Prnp (+/+)) compared to PrP knock-out (Prnp (-/-)) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrP(Sc)) in vitro and ex vivo, indicating a link between the two proteins...
August 30, 2017: Scientific Reports
Abhishek Asthana, Shounak Baksi, Ajay Ashok, Shilpita Karmakar, Najiba Mammadova, Robyn Kokemuller, Mary Heather Greenlee, Qingzhong Kong, Neena Singh
Prion disease-associated retinal degeneration is attributed to PrP-scrapie (PrP(Sc)), a misfolded isoform of prion protein (PrP(C)) that accumulates in the neuroretina. However, a lack of temporal and spatial correlation between PrP(Sc) and cytotoxicity suggests the contribution of host factors. We report retinal iron dyshomeostasis as one such factor. PrP(C) is expressed on the basolateral membrane of retinal-pigment-epithelial (RPE) cells, where it mediates uptake of iron by the neuroretina. Accordingly, the neuroretina of PrP-knock-out mice is iron-deficient...
August 29, 2017: Scientific Reports
Jesús R Requena, Holger Wille
The prion diseases, which include Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids (i.e., deer, elk, moose, and reindeer), bovine spongiform encephalopathy in cattle, as well as sheep and goat scrapie, are caused by the conversion of the cellular prion protein (PrP(C)) into a disease-causing conformer (PrP(Sc)). PrP(C) is a regular, GPI-anchored protein that is expressed on the cell surface of neurons and many other cell types. The structure of PrP(C) is well studied, based on analyses of recombinant PrP, which is thought to mimic the structure of native PrP(C)...
2017: Progress in Molecular Biology and Translational Science
Candace K Mathiason
Transmissible spongiform encephalopathies (TSEs), or prions, are neurodegenerative diseases that affect a variety of animal species, including humans. Cruetzfeldt-Jakob disease (CJD) in humans, sheep and goat scrapie, chronic wasting disease (CWD) of cervids, and transmissible mink encephalopathy (TME) of mink are classified as TSEs. According to the "protein-only" hypothesis (Prusiner, 1982),(1) prions are devoid of nucleic acids and consist of assemblies of misfolded host-encoded normal protein, the prion protein (PrP(C))...
2017: Progress in Molecular Biology and Translational Science
George A Carlson
Early genetic studies on scrapie, an infectious neurodegenerative disease of sheep that was adapted to mice, provided evidence in support of the hypothesis that the agent was a slow virus with a nucleic acid genome independent of the host. Particularly compelling support for an independent genome came from the existence of strains of scrapie agent, some of which were true breeding, while others appeared to mutate under selective pressure. Kuru, a neurodegenerative disease in the remote highlands of Papua New Guinea, had pathological changes similar to those in scrapie and also proved to be transmissible...
2017: Progress in Molecular Biology and Translational Science
Allison Kraus, Gregory J Raymond, Brent Race, Katrina J Campbell, Andrew G Hughson, Kelsie J Anson, Lynne D Raymond, Byron Caughey
Accumulation of fibrillar protein aggregates is a hallmark of many diseases. While numerous proteins form fibrils by prion-like seeded polymerization in vitro, only some are transmissible and pathogenic in vivo To probe the structural features that confer transmissibility to prion protein (PrP) fibrils, we have analyzed synthetic PrP amyloids with or without the human prion disease-associated P102L mutation. The formation of infectious prions from PrP molecules in vitro has required cofactors and/or unphysiological denaturing conditions...
August 23, 2017: Journal of Virology
Enrico Caldarulo, Alessandro Barducci, Kurt Wüthrich, Michele Parrinello
In transmissible spongiform encephalopathies (TSEs), which are lethal neurodegenerative diseases that affect humans and a wide range of other mammalian species, the normal "cellular" prion protein ([Formula: see text]) is transformed into amyloid aggregates representing the "scrapie form" of the protein ([Formula: see text]). Continued research on this system is of keen interest, since new information on the physiological function of [Formula: see text] in healthy organisms is emerging, as well as new data on the mechanism of the transformation of [Formula: see text] to [Formula: see text] In this paper we used two different approaches: a combination of the well-tempered ensemble (WTE) and parallel tempering (PT) schemes and metadynamics (MetaD) to characterize the conformational free-energy surface of [Formula: see text] The focus of the data analysis was on an 11-residue polypeptide segment in mouse [Formula: see text](121-231) that includes the [Formula: see text]2-[Formula: see text]2 loop of residues 167-170, for which a correlation between structure and susceptibility to prion disease has previously been described...
August 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
Nicolas Privat, Etienne Levavasseur, Serfildan Yildirim, Samia Hannaoui, Jean-Philippe Brandel, Jean-Louis Laplanche, Vincent Béringue, Danielle Seilhean, Stéphane Haïk
Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrPSc). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrPSc deposits within the brain and the spongiform lesions they induce...
August 15, 2017: Journal of Biological Chemistry
Ben A Wall, Mark E Arnold, Devi Radia, Will Gilbert, Angel Ortiz-Pelaez, Katharina Dc Stärk, Ed Van Klink, Javier Guitian
Transmissible spongiform encephalopathies (TSEs) are an important public health concern. Since the emergence of bovine spongiform encephalopathy (BSE) during the 1980s and its link with human Creutzfeldt-Jakob disease, active surveillance has been a key element of the European Union's TSE control strategy. Success of this strategy means that now, very few cases are detected compared with the number of animals tested. Refining surveillance strategies would enable resources to be redirected towards other public health priorities...
August 10, 2017: Euro Surveillance: Bulletin Européen sur les Maladies Transmissibles, European Communicable Disease Bulletin
Emmanuelle Boilan, Virginie Winant, Elise Dumortier, Benaissa ElMoualij, Pascale Quatresooz, Heinz D Osiewacz, Florence Debacq-Chainiaux, Olivier Toussaint
Prion protein (PrP) is essentially known for its capacity to induce neurodegenerative prion diseases in mammals caused by a conformational change in its normal cellular isoform (PrP(C)) into an infectious and disease-associated misfolded form, called scrapie isoform (PrP(Sc)). Although its sequence is highly conserved, less information is available on its physiological role under normal conditions. However, increasing evidence supports a role for PrP(C) in the cellular response to oxidative stress. In the present study, a new link between PrP and senescence is highlighted...
August 8, 2017: Mechanisms of Ageing and Development
Veronique Perrier, Thibaut Imberdis, Pierre-Andre Lafon, Marina Cefis, Yunyun Wang, Elisabeth Huetter, Jacques-Damien Arnaud, Teresa Alvarez-Martinez, Naig Le Guern, Guillaume Maquart, Laurent Lagrost, Catherine Desrumaux
Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apolipoprotein B-containing lipoproteins, i.e. the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo...
August 1, 2017: Journal of Lipid Research
Brent Race, Martin Jeffrey, Gillian McGovern, David Dorward, Bruce Chesebro
In most human and animal prion diseases the abnormal disease-associated prion protein (PrPSc) is deposited as non-amyloid aggregates in CNS, spleen and lymphoid organs. In contrast, in humans and transgenic mice with PrP mutations which cause expression of PrP lacking a glycosylphosphatidylinositol (GPI)-anchor, most PrPSc is in the amyloid form. In transgenic mice expressing only anchorless PrP (tg anchorless), PrPSc is deposited not only in CNS and lymphoid tissues, but also in extraneural tissues including heart, brown fat, white fat, and colon...
July 4, 2017: Prion
James A Carroll, Brent Race, Katie Phillips, James F Striebel, Bruce Chesebro
Neuroinflammation is a prominent component of several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, tauopathies, amyotrophic lateral sclerosis and prion diseases. In such conditions, the ability to decrease neuroinflammation by drug therapy may influence disease progression. Statins have been used to treat hyperlipidemia as well as reduce neuroinflammation and oxidative stress in various tissues. In previous studies, treatment of scrapie-infected mice with the type 1 statins, simvastatin or pravastatin, showed a small beneficial effect on survival time...
August 2017: Journal of General Virology
K C Gough, C A Baker, B C Maddison
Scrapie infectivity enters the environment via a multiplicity of routes from infected animals. Environmentally associated scrapie persists on farms when infected animals have been removed and is particularly resistant to disinfection. Infectivity within the farm is not adequately removed by current recommended guidelines for farm decontamination. We describe an in vitro method for modelling decontamination, specifically the removal of scrapie prions from the surface of concrete fomites within buildings that have housed scrapie infected animals...
August 2017: Veterinary Microbiology
Kelcey D Dinkel, David A Schneider, Juan F Muñoz-Gutiérrez, Valerie R McElliott, James B Stanton
Prion diseases are fatal neurodegenerative disorders by which the native cellular prion protein (PrP(C)) is misfolded into an accumulating, disease-associated isoform (PrP(D)). To improve the understanding of prion pathogenesis and develop effective treatments, it is essential to elucidate factors contributing to cellular permissiveness. We previously isolated five clones from an immortalized subline of ovine microglia, two of which had demonstrated differential permissiveness to a natural isolate of sheep scrapie and distinct transcriptomic profiles...
July 25, 2017: Virus Research
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