scholarly journals Transmissible spongiform encephalopathy strain, PrP genotype and brain region all affect the degree of glycosylation of PrPSc

2005 ◽  
Vol 86 (1) ◽  
pp. 241-246 ◽  
Author(s):  
Robert A. Somerville ◽  
Scott Hamilton ◽  
Karen Fernie
Keyword(s):  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Infectious Agent ◽  
Host Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Major Influence ◽  
Spongiform Encephalopathy ◽  
Phenotypic Properties ◽  
Spongiform Encephalopathies ◽  
Diagnostic Potential

Transmissible spongiform encephalopathies (TSEs), sometimes known as prion diseases, are caused by an infectious agent whose molecular properties have not been determined. Traditionally, different strains of TSE diseases are characterized by a series of phenotypic properties after passage in experimental animals. More recently it has been recognized that diversity in the degree to which an abnormal form of the host protein PrP, denoted PrPSc, is glycosylated and the migration of aglycosyl forms of PrPSc on immunoblots may have some differential diagnostic potential. It has been recognized that these factors are affected by the strain of TSE agent but also by other factors, e.g. location within the brain. This study shows in some cases, but not others, that host PrP genotype has a major influence on the degree of PrPSc glycosylation and migration on gels and provides further evidence of the effect of brain location. Accordingly both the degree of glycosylation and the apparent molecular mass of PrPSc may be of some value for differential diagnosis between TSE strains, but only when host effects are taken into account. Furthermore, the data inform the debate about how these differences arise, and favour hypotheses proposing that TSE agents affect glycosylation of PrP during its biosynthesis.

scholarly journals Characterization of the effect of heat on agent strains of the transmissible spongiform encephalopathies

2011 ◽  
Vol 92 (7) ◽  
pp. 1738-1748 ◽  
Author(s):  
Robert A. Somerville ◽  
Nicola Gentles
Keyword(s):  
Conformational Changes ◽  
High Resistance ◽  
Thermal Inactivation ◽  
Transmissible Spongiform Encephalopathy ◽  
Infectious Agent ◽  
Host Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Heat Inactivation ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies

The causal agents of the transmissible spongiform encephalopathy (TSE) diseases, sometimes called prion diseases, are characterized by high resistance to inactivation with heat. Results from thermal inactivation experiments on nine TSE strains, seven passaged in two PrP genotypes, showed differences in sensitivity to heat inactivation ranging over 17 °C. In addition, the rate of inactivation with increasing temperature varied between TSE models. In some cases passage in an alternative PrP genotype had little effect on the resulting inactivation properties, but for others the infectious agent was inactivated at lower temperatures. No strain with higher thermostability properties was selected. The effect of mixing two TSE strains, to see whether their properties were affected through interaction with each other, was also examined. The results showed that both strains behaved as expected from the behaviour of the unmixed controls, and that the strain responsible for inducing TSE disease could be identified. There was no evidence of a direct effect on intrinsic strain properties. Overall, the results illustrate the diversity in properties of TSE strains. They require intrinsic molecular properties of TSE agents to accommodate high resistance to inactivation and a mechanism, independent of the host, to directly encode these differences. These findings are more readily reconciled with models of TSE agents with two separate components, one of which is independent of the host and comprises a TSE-specific nucleic acid, than with models based solely on conformational changes to a host protein.

An overview of transmissible spongiform encephalopathies

2004 ◽  
Vol 5 (2) ◽  
pp. 103-124 ◽  
Author(s):  
K. Takemura ◽  
M. Kahdre ◽  
D. Joseph ◽  
A. Yousef ◽  
S. Sreevatsan
Keyword(s):  
Prion Diseases ◽  
Infectious Agent ◽  
Transmissible Spongiform Encephalopathies ◽  
Causal Mechanism ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Disease Diagnostics ◽  
New Variant ◽  
Jakob Disease ◽  
Underlying Mechanisms

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders of humans and animals associated with an accumulation of abnormal isoforms of prion protein (PrP) in nerve cells. The pathogenesis of TSEs involves conformational conversions of normal cellular PrP (PrPc) to abnormal isoforms of PrP (PrPSc). While the protein-only hypothesis has been widely accepted as a causal mechanism of prion diseases, evidence from more recent research suggests a possible involvement of other cellular component(s) or as yet undefined infectious agent(s) in PrP pathogenesis. Although the underlying mechanisms of PrP strain variation and the determinants of interspecies transmissibility have not been fully elucidated, biochemical and molecular findings indicate that bovine spongiform encephalopathy in cattle and new-variant Creutzfeldt–Jakob disease in humans are caused by indistinguishable etiological agent(s). Cumulative evidence suggests that there may be risks of humans acquiring TSEs via a variety of exposures to infected material. The development of highly precise ligands is warranted to detect and differentiate strains, allelic variants and infectious isoforms of these PrPs. This article describes the general features of TSEs and PrP, the current understanding of their pathogenesis, recent advances in prion disease diagnostics, and PrP inactivation.

How to Limit the Spread of Creutzfeldt-Jakob Disease

1996 ◽  
Vol 17 (8) ◽  
pp. 521-528
Author(s):  
Dominique Dormont
Keyword(s):  
Blood Donation ◽  
Transmissible Spongiform Encephalopathy ◽  
Infected Individual ◽  
Experimental Models ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Corneal Grafting ◽  
Jakob Disease ◽  
Spleen And Lymph Nodes

AbstractTransmissible spongiform encephalopathies are rare lethal diseases induced in humans and animals by unconventional agents called transmissible spongiform encephalopathy agents (TSEAs), virions, or prions. Several cases of iatrogenic Creutzfeldt-Jakob disease (CJD) have been reported in the literature after neuro-surgery, treatment with pituitary-derived hormones, corneal grafting, and use of dura mater lyophilisates. In a given infected individual, TSEA-associated infectiousness depends on the nature of the organ: the central nervous system has the highest infectiousness, spleen and lymph nodes a medium infectiousness, and organs such as bone, skin, or skeletal muscles do not harbor any detectable infectiousness in experimental models. Transmissible spongiform encephalopathy/prions have unconventional properties; in particular, they resist almost all the chemical and physical processes that inactivate conventional viruses. Therefore, prevention of CJD agent transmission must be taken into account in daily hospital practice. Efficient sterilization procedures should be determined. In tissue and blood donation, donors with a neurologic history must be excluded, and patients treated with pituitary-derived hormones should be considered potentially infected with TSEA and excluded.

scholarly journals Sympathetic Prions

2001 ◽  
Vol 1 ◽  
pp. 555-556 ◽  
Author(s):  
Markus Glatzel
Keyword(s):  
Gastrointestinal Tract ◽  
Injection Site ◽  
Peripheral Nerves ◽  
Infectious Agent ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Membrane Glycoprotein ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
The Brain

Transmissible spongiform encephalopathies are a group of invariably fatal neurodegenerative diseases. The infectious agent is termed prion and is thought to be composed of a modified protein (PrPSc or PrPRES), a protease-resistant conformer of the normal host-encoded membrane glycoprotein, PrPC[1]. Bovine spongiform encephalopathy, scrapie of sheep, and Creutzfeldt-Jakob disease are among the most notable transmissible spongiform encephalopathies. Prions are most efficiently propagated trough intracerebral inoculation, yet the entry point of the infectious agent is often through peripheral sites like the gastrointestinal tract[2,3]. The process by which prions invade the brain is termed neuroinvasion[4]. We and others have speculated that, depending on the amount of infectious agent injected, the injection site, and the strain of prions employed, neuroinvasion can occur either directly via peripheral nerves or first through the lymphoreticular system and then via peripheral nerves[5].

Prions: Protein Aggregation and Infectious Diseases

2009 ◽  
Vol 89 (4) ◽  
pp. 1105-1152 ◽  
Author(s):  
Adriano Aguzzi ◽  
Anna Maria Calella
Keyword(s):  
Protein Aggregation ◽  
Prion Diseases ◽  
Physiological Role ◽  
Infectious Agent ◽  
Normal Function ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Pathological Features ◽  
Spongiform Encephalopathies

Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPCis necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPCmay help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.

scholarly journals Prion Type-Dependent Deposition ofPRNPAllelic Products in Heterozygous Sheep

2015 ◽  
Vol 90 (2) ◽  
pp. 805-812 ◽  
Author(s):  
J. P. M. Langeveld ◽  
J. G. Jacobs ◽  
N. Hunter ◽  
L. J. M. van Keulen ◽  
F. Lantier ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Transmissible Spongiform Encephalopathy ◽  
Infected Sheep ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Sequence Variants ◽  
Spongiform Encephalopathies

ABSTRACTSusceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, PrP allotype composition in protease-resistant prion protein (PrPres) from brain of heterozygous ARR/VRQ scrapie-infected sheep was compared with that of BSE-infected sheep with a similar genotype. A triplex Western blotting technique was used to estimate the two allotype PrP fractions in PrPresmaterial from BSE-infected ARR/VRQ sheep. PrPresin BSE contained equimolar amounts of VRQ- and ARR-PrP, which contrasts with the excess (>95%) VRQ-PrP fraction found in PrP in scrapie. This is evidence that transmissible spongiform encephalopathy (TSE) agent properties alone, perhaps structural aspects of prions (such as PrP amino acid sequence variants and PrP conformational state), determine the polymorphic dependence of the PrPresaccumulation process in prion formation as well as the disease-associated phenotypic expressions in the host.IMPORTANCETransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative and transmissible diseases caused by prions. Amino acid sequence variants of the prion protein (PrP) determine transmissibility in the hosts, as has been shown for classical scrapie in sheep. Each individual produces a separate PrP molecule from its two PrP gene copies. Heterozygous scrapie-infected sheep that produce two PrP variants associated with opposite scrapie susceptibilities (136V-PrP variant, high; 171R-PrP variant, very low) contain in their prion material over 95% of the 136V PrP variant. However, when these sheep are infected with prions from cattle (bovine spongiform encephalopathy [BSE]), both PrP variants occur in equal ratios. This shows that the infecting prion type determines the accumulating PrP variant ratio in the heterozygous host. While the host's PrP is considered a determining factor, these results emphasize that prion structure plays a role during host infection and that PrP variant involvement in prions of heterozygous carriers is a critical field for understanding prion formation.

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.

Possible origin of the scrapie genome in small endogenous RNAs; studies on eight candidate species in 263K scrapie-infected hamster brain

2019 ◽  
Author(s):  
Eleanor Barnard ◽  
Kathryn Estibeiro ◽  
Rory Duncan ◽  
Janet Baird ◽  
David Fettes ◽  
...  
Keyword(s):  
Infectious Agent ◽  
Etiologic Agent ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Systematic Analysis ◽  
Spongiform Encephalopathies ◽  
Rna Molecules ◽  
Infected Hamster ◽  
Molecular Variants ◽  
Initial Work

SUMMARYThe identity of the etiologic agent of the transmissible spongiform encephalopathies (TSEs), including bovine spongiform encephalopathy (BSE), scrapie and Creutzfeldt-Jakob disease (CJD), remains unknown. While much attention has been given to the hypothesis that the TSEs may be caused by a proteinaceous infectious agent or ‘prion’, there is considerable evidence to suggest that this hypothesis is incomplete. We have pursued an alternative contention: that the etiologic agent comprises in part a modified and replicating form of an endogenous nucleic acid, probably RNA. The ‘endovirus’ hypothesis contends that the parental molecule is most likely to be a small and highly-structured cellular RNA that can convert to a replicating molecule by a finite number of nucleotide sequence changes. We have begun a systematic analysis of candidate molecular species present in hamster brain infected with scrapie strain 263K. Initial work focussed on the 7S group of small RNAs. Examination of 7-2, 7SK and 7SL failed to reveal differences in abundance and/or sequence between normal and scrapie (263K)-infected hamster brain. Inspection of other possible candidates, including U3, H1/8-2 and novel molecules KR1, nu1 and nu2, similarly failed to provide evidence for scrapie-specific molecular variants; alterations to the KR1 sequence failed to correlate with disease. We present sequences of hamster RNAs 7-2, 7SK, 7SL, H1/8-2, U3, nu1, nu2 and KR1. Together our data so far fail to contradict or confirm the hypothesis, while arguing that the major species of these 8 RNA molecules are unlikely to correspond to the etiologic agent of the TSEs.

scholarly journals Lymphotoxin-α- and Lymphotoxin-β-Deficient Mice Differ in Susceptibility to Scrapie: Evidence against Dendritic Cell Involvement in Neuroinvasion

2002 ◽  
Vol 76 (9) ◽  
pp. 4357-4363 ◽  
Author(s):  
Michael B. A. Oldstone ◽  
Richard Race ◽  
Diane Thomas ◽  
Hanna Lewicki ◽  
Dirk Homann ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Oral Intake ◽  
Infectious Agent ◽  
Lymphoid Cells ◽  
Current Evidence ◽  
Spongiform Encephalopathy ◽  
Lymphoid Tissues ◽  
Mesenteric Lymph Nodes

ABSTRACT Transmissible spongiform encephalopathy or prion diseases are fatal neurodegenerative disorders of humans and animals often initiated by oral intake of an infectious agent. Current evidence suggests that infection occurs initially in the lymphoid tissues and subsequently in the central nervous system (CNS). The identity of infected lymphoid cells remains controversial, but recent studies point to the involvement of both follicular dendritic cells (FDC) and CD11c+ lymphoid dendritic cells. FDC generation and maintenance in germinal centers is dependent on lymphotoxin alpha (LT-α) and LT-β signaling components. We report here that by the oral route, LT-α −/− mice developed scrapie while LT-β −/− mice did not. Furthermore, LT-α −/− mice had a higher incidence and shorter incubation period for developing disease following inoculation than did LT-β −/− mice. Transplantation of lymphoid tissues from LT-β −/− mice, which have cervical and mesenteric lymph nodes, into LT-α −/− mice, which do not, did not alter the incidence of CNS scrapie. In other studies, a virus that is tropic for and alters functions of CD11c+ cells did not alter the kinetics of neuroinvasion of scrapie. Our results suggest that neither FDC nor CD11c+ cells are essential for neuroinvasion after high doses of RML scrapie. Further, it is possible that an as yet unidentified cell found more abundantly in LT-α −/− than in LT-β −/− mice may assist in the amplification of scrapie infection in the periphery and favor susceptibility to CNS disease following peripheral routes of infection.

Human Prion Diseases

2013 ◽  
pp. 149-160
Author(s):  
James W. Ironside ◽  
Matthew P. Frosch ◽  
Bernardino Ghetti
Keyword(s):  
Prion Diseases ◽  
Neuronal Loss ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Pituitary Hormone ◽  
Human Pituitary ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Prnp Codon ◽  
Codon 129

This chapter describes and illustrates the neuropathology of prion diseases, also known as transmissible spongiform encephalopathies. These diseases are characterized pathologically by varying combinations of spongiform change, neuronal loss, reactive gliosis, and prion protein (PrP) deposition. The morphologic pattern depends on the etiology of the disease and the genotype of the patient. Different clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (CJD) have been described depending on the PRNP codon 129 genotype and the PrP isotype. A novel form known as variably protease-sensitive prionopathy has been recently identified. Familial prion diseases include familial CJD, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Over 40 different PRNP mutations have been identified. Acquired prion diseases include Kuru; iatrogenic CJD, particularly in recipients of contaminated human pituitary hormone, and variant CJD, which seems closely related to bovine spongiform encephalopathy.

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