scholarly journals Transition of the prion protein from a structured cellular form (PrP C ) to the infectious scrapie agent (PrP Sc )

2019 ◽  
Vol 28 (12) ◽  
pp. 2055-2063 ◽  
Author(s):  
Pravas K. Baral ◽  
Jiang Yin ◽  
Adriano Aguzzi ◽  
Michael N. G. James
Keyword(s):  
Prion Protein ◽  
Scrapie Agent

Immunisation with a synthetic prion protein-derived peptide prolongs survival times of mice orally exposed to the scrapie agent

2003 ◽  
Vol 350 (3) ◽  
pp. 187-189 ◽  
Author(s):  
Anja Schwarz ◽  
Oliver Krätke ◽  
Michael Burwinkel ◽  
Constanze Riemer ◽  
Julia Schultz ◽  
...  
Keyword(s):  
Prion Protein ◽  
Survival Times ◽  
Scrapie Agent

scholarly journals Scrapie-Induced Defects in Learning and Memory of Transgenic Mice Expressing Anchorless Prion Protein Are Associated with Alterations in the Gamma Aminobutyric Acid-Ergic Pathway

2008 ◽  
Vol 82 (20) ◽  
pp. 9890-9899 ◽  
Author(s):  
Matthew J. Trifilo ◽  
Manuel Sanchez-Alavez ◽  
Laura Solforosi ◽  
Joie Bernard-Trifilo ◽  
Stefan Kunz ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Learning And Memory ◽  
Prion Protein ◽  
Gabaa Receptors ◽  
Memory Loss ◽  
Long Term Potentiation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Scrapie Agent

ABSTRACT After infection with RML murine scrapie agent, transgenic (tg) mice expressing prion protein (PrP) without its glycophosphatidylinositol (GPI) membrane anchor (GPI−/− PrP tg mice) continue to make abundant amounts of the abnormally folded disease-associated PrPres but have a normal life span. In contrast, all age-, sex-, and genetically matched mice with a GPI-anchored PrP become moribund and die due to a chronic progressive neurodegenerative disease by 160 days after RML scrapie agent infection. We report here that infected GPI−/− PrP tg mice, although free from progressive neurodegenerative disease of the cerebellum and extrapyramidal and pyramidal systems, nevertheless suffer defects in learning and memory, long-term potentiation, and neuronal excitability. Such dysfunction increases over time and is associated with an increase in gamma aminobutyric acid (GABA) inhibition but not loss of excitatory glutamate/N-methyl-d-aspartic acid. Enhanced deposition of abnormally folded infectious PrP (PrPsc or PrPres) in the central nervous system (CNS) localizes with GABAA receptors. This occurs with minimal evidence of CNS spongiosis or apoptosis of neurons. The use of monoclonal antibodies reveals an association of PrPres with GABAA receptors. Thus, the clinical defects of learning and memory loss in vivo in GPI−/− PrP tg mice infected with scrapie agent may likely involve the GABAergic pathway.

scholarly journals Neuron-specific expression of a hamster prion protein minigene in transgenic mice induces susceptibility to hamster scrapie agent

Neuron ◽  
1995 ◽  
Vol 15 (5) ◽  
pp. 1183-1191 ◽  
Author(s):  
Richard E. Race ◽  
Suzette A. Priola ◽  
Richard A. Bessen ◽  
Darwin Ernst ◽  
Janel Dockter ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Specific Expression ◽  
Scrapie Agent

scholarly journals Transmission of the atypical/Nor98 scrapie agent to Suffolk sheep with VRQ/ARQ, ARQ/ARQ, and ARQ/ARR genotypes

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246503
Author(s):  
Eric D. Cassmann ◽  
Najiba Mammadova ◽  
S. Jo Moore ◽  
Sylvie Benestad ◽  
Justin J. Greenlee
Keyword(s):  
Prion Protein ◽  
Transmissible Spongiform Encephalopathy ◽  
Brain Homogenate ◽  
Classical Scrapie ◽  
Spongiform Encephalopathy ◽  
Scrapie Agent ◽  
Suffolk Sheep

Scrapie is a transmissible spongiform encephalopathy that occurs in sheep. Atypical/Nor98 scrapie occurs in sheep that tend to be resistant to classical scrapie and it is thought to occur spontaneously. The purpose of this study was to test the transmission of the Atypical/Nor98 scrapie agent in three genotypes of Suffolk sheep and characterize the distribution of misfolded prion protein (PrPSc). Ten sheep were intracranially inoculated with brain homogenate from a sheep with Atypical/Nor98 scrapie. All sheep with the ARQ/ARQ and ARQ/ARR genotypes developed Atypical/Nor98 scrapie confirmed by immunohistochemistry, and one sheep with the VRQ/ARQ genotype had detectable PrPSc consistent with Atypical/Nor98 scrapie at the experimental endpoint of 8 years. Sheep with mild early accumulations of PrPSc in the cerebellum had concomitant retinal PrPSc. Accordingly, large amounts of retinal PrPSc were identified in clinically affected sheep and sheep with dense accumulations of PrPSc in the cerebellum.

scholarly journals Expanding spectrum of prion diseases

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

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

scholarly journals Multiple Amino Acid Residues within the Rabbit Prion Protein Inhibit Formation of Its Abnormal Isoform

2003 ◽  
Vol 77 (3) ◽  
pp. 2003-2009 ◽  
Author(s):  
Ina Vorberg ◽  
Martin H. Groschup ◽  
Eberhard Pfaff ◽  
Suzette A. Priola
Keyword(s):  
Amino Acid ◽  
Prion Protein ◽  
Neurological Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Amino Acid Residues ◽  
Spongiform Encephalopathies ◽  
Prolonged Incubation ◽  
Culture Cells ◽  
Scrapie Agent

ABSTRACT Transmissible spongiform encephalopathies (TSEs) are neurological diseases that are associated with the conversion of the normal host-encoded prion protein (PrP-sen) to an abnormal protease-resistant form, PrP-res. Transmission of the TSE agent from one species to another is usually inefficient and accompanied by a prolonged incubation time. Species barriers to infection by the TSE agent are of particular importance given the apparent transmission of bovine spongiform encephalopathy to humans. Among the few animal species that appear to be resistant to infection by the TSE agent are rabbits. They survive challenge with the human kuru and Creutzfeldt-Jakob agents as well as with scrapie agent isolated from sheep or mice. Species barriers to the TSE agent are strongly influenced by the PrP amino acid sequence of both the donor and recipient animals. Here we show that rabbit PrP-sen does not form PrP-res in murine tissue culture cells persistently infected with the mouse-adapted scrapie agent. Unlike other TSE species barriers that have been studied, critical amino acid residues that inhibit PrP-res formation are located throughout the rabbit PrP sequence. Our results suggest that the resistance of rabbits to infection by the TSE agent is due to multiple rabbit PrP-specific amino acid residues that result in a PrP structure that is unable to refold to the abnormal isoform associated with disease.

scholarly journals Distribution of prion protein in the ileal Peyer’s patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent

2000 ◽  
Vol 81 (9) ◽  
pp. 2327-2337 ◽  
Author(s):  
Ragna Heggebø ◽  
Charles McL. Press ◽  
Gjermund Gunnes ◽  
Kai Inge Lie ◽  
Michael A. Tranulis ◽  
...  
Keyword(s):  
Prion Protein ◽  
Central Zone ◽  
Neck Region ◽  
Peyer’S Patch ◽  
Peyer's Patch ◽  
Scrapie Agent ◽  
Amplification System ◽  
Brain Material ◽  
Vascular Structures ◽  
Signal Amplification System

A sensitive immunohistochemical procedure was used to investigate the presence of prion protein (PrP) in the ileal Peyer’s patch of PrP-genotyped lambs, including scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. The tyramide signal amplification system was used to enhance the sensitivity of conventional immunohistochemical procedures to show that PrP was widely distributed in the enteric nervous plexus supplying the gut wall. In scrapie-free lambs, PrP was also detected in scattered cells in the lamina propria and in the dome and interfollicular areas of the Peyer’s patch. In the follicles, staining for PrP was mainly confined to the capsule and cells associated with vascular structures in the light central zone. In lambs naturally exposed to the scrapie agent, staining was prominent in the dome and neck region of the follicles and was also found to be associated with the follicle-associated epithelium. Similar observations were made in lambs that had received a single oral dose of scrapie-infected brain material from sheep with a homologous and heterologous PrP genotype 1 and 5 weeks previously. These studies show that the ileal Peyer’s patch in young sheep may be an important site of uptake of the scrapie agent and that the biology of this major gut-associated lymphoid tissue may influence the susceptibility to oral infection in sheep. Furthermore, these studies suggest that homology or heterology between PrP genotypes or the presence of PrP genotypes seldom associated with disease does not impede uptake of PrP.

scholarly journals Review: Update on Classical and Atypical Scrapie in Sheep and Goats

2018 ◽  
Vol 56 (1) ◽  
pp. 6-16 ◽  
Author(s):  
Justin J. Greenlee
Keyword(s):  
Prion Protein ◽  
Environmental Contamination ◽  
Protein Misfolding ◽  
Transmissible Spongiform Encephalopathy ◽  
Classical Scrapie ◽  
Spongiform Encephalopathy ◽  
Atypical Scrapie ◽  
Sheep And Goats ◽  
Scrapie Agent ◽  
Scrapie Strains

Scrapie is a naturally occurring transmissible spongiform encephalopathy (TSE) or prion disease of sheep and goats. Scrapie is a protein misfolding disease where the normal prion protein (PrPC) misfolds into a pathogenic form (PrPSc) that is highly resistant to enzymatic breakdown within the cell and accumulates, eventually leading to neurodegeneration. The amino acid sequence of the prion protein and tissue distribution of PrPSc within affected hosts have a major role in determining susceptibility to and potential environmental contamination with the scrapie agent. Many countries have genotype-based eradication programs that emphasize using rams that express arginine at codon 171 in the prion protein, which is associated with resistance to the classical scrapie agent. In classical scrapie, accumulation of PrPSc within lymphoid and other tissues facilitates environmental contamination and spread of the disease within flocks. A major distinction can be made between classical scrapie strains that are readily spread within populations of susceptible sheep and goats and atypical (Nor-98) scrapie that has unique molecular and phenotype characteristics and is thought to occur spontaneously in older sheep or goats. This review provides an overview of classical and atypical scrapie with consideration of potential transmission of classical scrapie to other mammalian hosts.

scholarly journals Molecular Analysis of the Abnormal Prion Protein during Coinfection of Mice by Bovine Spongiform Encephalopathy and a Scrapie Agent

2001 ◽  
Vol 75 (1) ◽  
pp. 107-114 ◽  
Author(s):  
Thierry G. M. Baron ◽  
Anne-Gaelle Biacabe
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Proteinase K ◽  
Spongiform Encephalopathy ◽  
Molecular Features ◽  
Electrophoretic Mobilities ◽  
Scrapie Agent ◽  
Scrapie Strain ◽  
Sheep Scrapie

ABSTRACT Molecular features of the proteinase K-resistant prion protein (PrP res) may discriminate among prion strains, and a specific signature could be found during infection by the infectious agent causing bovine spongiform encephalopathy (BSE). To investigate the molecular basis of BSE adaptation and selection, we established a model of coinfection of mice by both BSE and a sheep scrapie strain (C506M3). We now show that the PrP res features in these mice, characterized by glycoform ratios and electrophoretic mobilities, may be undistinguishable from those found in mice infected with scrapie only, including when mice were inoculated by both strains at the same time and by the same intracerebral inoculation route. Western blot analysis using different antibodies against sequences near the putative N-terminal end of PrP res also demonstrated differences in the main proteinase K cleavage sites between mice showing either the BSE or scrapie PrP res profile. These results, which may be linked to higher levels of PrP res associated with infection by scrapie, were similar following a challenge by a higher dose of the BSE agent during coinfection by both strains intracerebrally. Whereas PrP res extraction methods used allowed us to distinguish type 1 and type 2 PrP res, differing, like BSE and scrapie, by their electrophoretic mobilities, in the same brain region of some patients with Creutzfeldt-Jakob disease, analysis of in vitro mixtures of BSE and scrapie brain homogenates did not allow us to distinguish BSE and scrapie PrP res. These results suggest that the BSE agent, the origin of which remains unknown so far but which may have arisen from a sheep scrapie agent, may be hidden by a scrapie strain during attempts to identify it by molecular studies and following transmission of the disease in mice.

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