Physicochemical and biological characterizations of distinct strains of the transmissible mink encephalopathy agent

1994 ◽  
Vol 343 (1306) ◽  
pp. 413-414 ◽  
Keyword(s):  
Great Britain ◽  
Prion Proteins ◽  
The United States ◽  
Biological Properties ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Scrapie Agent ◽  
Transmissible Mink Encephalopathy ◽  
Sheep Scrapie ◽  
Disease Specific

Inoculation of the Stetsonville, Wisconsin source of transmissible mink encephalopathy (TME) into Syrian hamsters has identified two strains of the tme agent having distinct biological properties and producing disease-specific prion proteins (PrP tme ) having different physicochemical properties. Although several strains of the sheep scrapie agent have been identified in Great Britain, this is the first indication that agents producing transmissible spongiform encephalopathies in the United States also are capable of producing distinct strains.

COMPARING FOLDING MECHANISMS OF DIFFERENT PRION PROTEINS BY Gō MODEL

2013 ◽  
Vol 12 (08) ◽  
pp. 1341004
Author(s):  
XUE WU ◽  
TING FU ◽  
ZHI-LONG XIU ◽  
LIU YIN ◽  
JIN-GUANG WANG ◽  
...  
Keyword(s):  
Free Energy ◽  
Prion Protein ◽  
Energy Barrier ◽  
Prion Proteins ◽  
Coarse Grained ◽  
Transmissible Spongiform Encephalopathies ◽  
Free Energy Barrier ◽  
Spongiform Encephalopathies ◽  
Go Model ◽  
Folding Free Energy

Prions are associated with neurodegenerative diseases induced by transmissible spongiform encephalopathies. The infectious scrapie form is referred to as PrP Sc , which has conformational change from normal prion with predominant α-helical conformation to the abnormal PrP Sc that is rich in β-sheet content. Neurodegenerative diseases have been found from both human and bovine sources, but there are no reports about infected by transmissible spongiform encephalopathies from rabbit, canine and horse sources. Here we used coarse-grained Gō model to compare the difference among human, bovine, rabbit, canine, and horse normal (cellular) prion proteins. The denatured state of normal prion has relation with the conversion from normal to abnormal prion protein, so we used all-atom Gō model to investigate the folding pathway and energy landscape for human prion protein. Through using coarse-grained Gō model, the cooperativity of the five prion proteins was characterized in terms of calorimetric criterion, sigmoidal transition, and free-energy profile. The rabbit and horse prion proteins have higher folding free-energy barrier and cooperativity, and canine prion protein has slightly higher folding free-energy barrier comparing with human and bovine prion proteins. The results from all-atom Gō model confirmed the validity of C α-Gō model. The correlations of our results with previous experimental and theoretical researches were discussed.

Scrapie-associated PrP accumulation and agent replication: effects of sulphated glycosaminoglycan analogues

1994 ◽  
Vol 343 (1306) ◽  
pp. 399-404 ◽  
Keyword(s):  
Congo Red ◽  
Therapeutic Agents ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Scrapie Agent ◽  
Sulphated Glycosaminoglycans ◽  
Relative Potencies ◽  
Sulphated Glycosaminoglycan ◽  
Agent Replication

An abnormally protease-resistant and apparently neuropathogenic form of PrP accumulates in the brains of hosts with scrapie and related transmissible spongiform encephalopathies. Studies with scrapieinfected neuroblastom a cells have highlighted dramatic differences in the metabolism of the normal (protease-sensitive) and scrapie-associated (protease-resistant) isoforms of PrP. Furthermore, this model has been useful in identifying inhibitors of protease-resistant PrP accumulation and scrapie agent replication which are valuable as potential therapeutic agents and as probes of the mechanism of protease-resistant PrP formation. These inhibitors include the amyloid stain Congo red and certain sulphated glycans which are glycosaminoglycans themselves or glycosaminoglycan analogues. The relative potencies of various sulphated glycans correlate with their previously determ ined anti-scrapie activities in vivo , suggesting that the prophylactic effects of sulphated polyanions is due to inhibition of protease-resistant PrP accumulation. These and other observations suggest that an interaction of PrP with endogenous sulphated glycosaminoglycans or proteoglycans is important in protease-resistant PrP accumulation, and raise the possibility that therapies for transmissible spongiform encephalopathies and other amyloidoses could be based on blocking (pre)am yloid-glycosaminoglycan interactions.

scholarly journals Susceptibility of Cattle to First-passage Intracerebral Inoculation with Chronic Wasting Disease Agent from White-tailed Deer

2007 ◽  
Vol 44 (4) ◽  
pp. 487-493 ◽  
Author(s):  
A. N. Hamir ◽  
J. M. Miller ◽  
R. A. Kunkle ◽  
S. M. Hall ◽  
J. A. Richt
Keyword(s):  
Chronic Wasting Disease ◽  
Prion Diseases ◽  
Clinical Signs ◽  
Diagnostic Techniques ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Spongiform Encephalopathies ◽  
Disease Agent ◽  
Sheep Scrapie

Fourteen, 3-month-old calves were intracerebrally inoculated with the agent of chronic wasting disease (CWD) from white-tailed deer (CWDwtd) to compare the clinical signs and neuropathologic findings with those of certain other transmissible spongiform encephalopathies (TSE, prion diseases) that have been shown to be experimentally transmissible to cattle (sheep scrapie, CWD of mule deer [CWDmd], bovine spongiform encephalopathy [BSE], and transmissible mink encephalopathy). Two uninoculated calves served as controls. Within 26 months postinoculation (MPI), 12 inoculated calves had lost considerable weight and eventually became recumbent. Of the 12 inoculated calves, 11 (92%) developed clinical signs. Although spongiform encephalopathy (SE) was not observed, abnormal prion protein (PrPd) was detected by immunohistochemistry (IHC) and Western blot (WB) in central nervous system tissues. The absence of SE with presence of PrPd has also been observed when other TSE agents (scrapie and CWDmd) were similarly inoculated into cattle. The IHC and WB findings suggest that the diagnostic techniques currently used to confirm BSE would detect CWDwtd in cattle, should it occur naturally. Also, the absence of SE and a distinctive IHC pattern of CWDwtd and CWDmd in cattle suggests that it should be possible to distinguish these conditions from other TSEs that have been experimentally transmitted to cattle.

scholarly journals Structure analysis of human Prion protein involved in Sporadic Fatal Insomnia

2018 ◽  
Author(s):  
Philip J Camp ◽  
Pardis Tabaee Damavandi ◽  
Richard W Pickersgill ◽  
Martin T Dove
Keyword(s):  
Prion Protein ◽  
Prion Proteins ◽  
Transmissible Spongiform Encephalopathies ◽  
Human Form ◽  
Native Form ◽  
Spongiform Encephalopathies ◽  
Root Cause ◽  
Progressive Neurodegeneration ◽  
Human Prion Protein ◽  
Key Residues

AbstractPrion disorders are the root cause of Transmissible Spongiform Encephalopathies (TSE), a group of lethal diseases portrayed by progressive neurodegeneration and spongiosis. In recent years, researchers have come to understand that it is not the endogenous presence of Prions itself that causes neurodegeneration, but the amount of prion proteins that accumulates in the nervous tissue, leading them to exert neurotoxicity. More specifically, the cause of these disorders is mapped to several mutations that can bring the prion protein structure to a disordered permanent misfolded state. Our research is focused on Sporadic Fatal Insomnia (sFI), a rare TSE characterized by severe and chronic insomnia, leading to a life expectancy estimation of about two and a half years, from the onset of the first symptoms. The goal of this work was to analyze through computational studies the structure of the native human Prion Protein (PrPnat) and compare it with the toxic form (FI-Prion) which causes disease. Our findings show that the structure of the human mutant FI-Prion, responsible for Sporadic Fatal Insomnia is more flexible than the native human form PrPnat. Specific regions of the mutant seem to fluctuate more freely than the corresponding loops in the native form. We also identified amino acids Tyr128 and Met129 to be the key residues playing a major role in the manifestation of the disease. Therefore, we’ve learnt that the FI-Prion is more flexible than PrPnat. In addition, we also confirmed that sporadic fatal insomnia is undoubtedly an infectious disease.

scholarly journals Adaptation and Selection of Prion Protein Strain Conformations following Interspecies Transmission of Transmissible Mink Encephalopathy

2000 ◽  
Vol 74 (12) ◽  
pp. 5542-5547 ◽  
Author(s):  
Jason C. Bartz ◽  
Richard A. Bessen ◽  
Debbie McKenzie ◽  
Richard F. Marsh ◽  
Judd M. Aiken
Keyword(s):  
Incubation Period ◽  
Prion Protein ◽  
Prion Diseases ◽  
Interspecies Transmission ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Strain Adaptation ◽  
Transmissible Mink Encephalopathy ◽  
Selection Of

ABSTRACT Interspecies transmission of the transmissible spongiform encephalopathies (TSEs), or prion diseases, can result in the adaptation and selection of TSE strains with an expanded host range and increased virulence such as in the case of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease. To investigate TSE strain adaptation, we serially passaged a biological clone of transmissible mink encephalopathy (TME) into Syrian golden hamsters and examined the selection of distinct strain phenotypes and conformations of the disease-specific isoform of the prion protein (PrPSc). The long-incubation-period drowsy (DY) TME strain was the predominate strain, based on the presence of its strain-specific PrPSc following interspecies passage. Additional serial passages in hamsters resulted in the selection of the hyper (HY) TME PrPSc strain-dependent conformation and its short incubation period phenotype unless the passages were performed with a low-dose inoculum (e.g., 10−5 dilution), in which case the DY TME clinical phenotype continued to predominate. For both TME strains, the PrPSc strain pattern preceded stabilization of the TME strain phenotype. These findings demonstrate that interspecies transmission of a single cloned TSE strain resulted in adaptation of at least two strain-associated PrPScconformations that underwent selection until one type of PrPSc conformation and strain phenotype became predominant. To examine TME strain selection in the absence of host adaptation, hamsters were coinfected with hamster-adapted HY and DY TME. DY TME was able to interfere with the selection of the short-incubation HY TME phenotype. Coinfection could result in the DY TME phenotype and PrPSc conformation on first passage, but on subsequent passages, the disease pattern converted to HY TME. These findings indicate that during TSE strain adaptation, there is selection of a strain-specific PrPSc conformation that can determine the TSE strain phenotype.

scholarly journals Prion protein genetics: Host PrP control of TSE susceptibility

2005 ◽  
Vol 27 (4) ◽  
pp. 20-23
Author(s):  
Wilfred Goldmann
Keyword(s):  
Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Degenerative Disorders ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
Important Host ◽  
Disease Family ◽  
Sheep Scrapie

TSEs (transmissible spongiform encephalopathies) are fatal, degenerative disorders of the central nervous system. The best-known members of this disease family are sheep scrapie, cattle BSE (bovine spongiform encephalopathy) and human CJD (Creutzfeldt–Jakob disease). By far the most important host gene in TSEs is the PrP (prion protein) gene. It modulates TSE susceptibility at many levels and is the crucial element in the treatment and eradication of these diseases. This article will highlight the advances in our understanding of PrP genetics in animals and man.

scholarly journals Structure analysis of human Prion protein involved in Sporadic Fatal Insomnia

2019 ◽  
Author(s):  
Pardis Tabaee Damavandi
Keyword(s):  
Prion Protein ◽  
Prion Proteins ◽  
Transmissible Spongiform Encephalopathies ◽  
Human Form ◽  
Native Form ◽  
Spongiform Encephalopathies ◽  
Root Cause ◽  
Progressive Neurodegeneration ◽  
Human Prion Protein ◽  
Key Residues

Prion disorders are the root cause of Transmissible Spongiform Encephalopathies (TSE), a group of lethal diseases portrayed by progressive neurodegeneration and spongiosis. In recent years, researchers have come to understand that it is not the endogenous presence of Prions itself that causes neurodegeneration, but the amount of prion proteins that accumulates in the nervous tissue, leading them to exert neurotoxicity. More specifically, the cause of these disorders is mapped to several mutations that can bring the prion protein structure to a disordered permanent misfolded state. Our research is focused on Sporadic Fatal Insomnia (sFI), a rare TSE characterized by severe and chronic insomnia, leading to a life expectancy estimation of about two and a half years, from the onset of the first symptoms. The goal of this work was to analyze through computational studies the structure of the native human Prion Protein (PrPnat) and compare it with the toxic form (FI-Prion) which causes disease. Our findings show that the structure of the human mutant FI-Prion, responsible for Sporadic Fatal Insomnia is more flexible than the native human form PrPnat. Specific regions of the mutant seem to fluctuate more freely than the corresponding loops in the native form. We also identified amino acids Tyr128 and Met129 to be the key residues playing a major role in the manifestation of the disease. Therefore, we’ve learnt that the FI-Prion is more flexible than PrPnat. In addition, we also confirmed that sporadic fatal insomnia is undoubtedly an infectious disease.

scholarly journals Stability of BSE infectivity towards heat treatment even after proteolytic removal of prion protein

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Jan P. M. Langeveld ◽  
Anne Balkema-Buschmann ◽  
Dieter Becher ◽  
Achim Thomzig ◽  
Romolo Nonno ◽  
...  
Keyword(s):  
Heat Treatment ◽  
Prion Protein ◽  
Bovine Brain ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Similar Treatment ◽  
Bank Voles ◽  
Before And After ◽  
Sheep Scrapie

AbstractThe unconventional infectious agents of transmissible spongiform encephalopathies (TSEs) are prions. Their infectivity co-appears with PrPSc, aberrant depositions of the host’s cellular prion protein (PrPC). Successive heat treatment in the presence of detergent and proteolysis by a keratinase from Bacillus licheniformis PWD-1 was shown before to destroy PrPSc from bovine TSE (BSE) and sheep scrapie diseased brain, however data regarding expected reduction of infectivity were still lacking. Therefore, transgenic Tgbov XV mice which are highly BSE susceptible were used to quantify infectivity before and after the bovine brain treatment procedure. Also four immunochemical analyses were applied to compare the levels of PrPSc. After heating at 115 °C with or without subsequent proteolysis, the original BSE infectivity of 106.2–6.4 ID50 g−1 was reduced to a remaining infectivity of 104.6–5.7 ID50 g−1 while strain characteristics were unaltered, even after precipitation with methanol. Surprisingly, PrPSc depletion was 5–800 times higher than the loss of infectivity. Similar treatment was applied on other prion strains, which were CWD1 in bank voles, 263 K scrapie in hamsters and sheep PG127 scrapie in tg338 ovinized mice. In these strains however, infectivity was already destroyed by heat only. These findings show the unusual heat resistance of BSE and support a role for an additional factor in prion formation as suggested elsewhere when producing prions from PrPC. Leftover material in the remaining PrPSc depleted BSE preparation offers a unique substrate for searching additional elements for prion infectivity and improving our concept about the nature of prions.

scholarly journals Epidemiological analysis of data for scrapie in Great Britain

2005 ◽  
Vol 134 (2) ◽  
pp. 359-367 ◽  
Author(s):  
T. J. HAGENAARS ◽  
C. A. DONNELLY ◽  
N. M. FERGUSON
Keyword(s):  
Great Britain ◽  
Selective Breeding ◽  
Large Fraction ◽  
Epidemiological Studies ◽  
Transmissible Spongiform Encephalopathies ◽  
Limited Data ◽  
Spongiform Encephalopathies ◽  
Sheep Population ◽  
Epidemiological Analysis ◽  
Control And Eradication

In recent years, the control or eradication of scrapie and any other transmissible spongiform encephalopathies (TSEs) possibly circulating in the sheep population has become a priority in Britain and elsewhere in Europe. A better understanding of the epidemiology of scrapie would greatly aid the development and evaluation of control and eradication strategies. Here we bound the range of key epidemiological parameters using a combination of relatively detailed pathogenesis and demography data, more limited data on susceptibility and incubation times, and recent survey data on scrapie incidence in Great Britain. These data are simultaneously analysed using mathematical models describing scrapie transmission between sheep and between flocks. Our analysis suggests that occurrence of scrapie in a flock typically provokes changes in flock management that promote termination of the outbreak, such as the adoption of selective breeding, and that a large fraction of cases (possibly over 80%) goes undetected. We show that the data analysed are consistent with the within-flock reproduction number of scrapie lying in the range 1·5–6, consistent with previous epidemiological studies.

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