scholarly journals Expression of doppel in the CNS of mice does not modulate transmissible spongiform encephalopathy disease

2002 ◽  
Vol 83 (3) ◽  
pp. 705-711 ◽  
Author(s):  
Nadia L. Tuzi ◽  
Elaine Gall ◽  
David Melton ◽  
Jean C. Manson
Keyword(s):  
Late Onset ◽  
Transmissible Spongiform Encephalopathy ◽  
Structural Similarity ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Naturally Occurring ◽  
Prp Gene ◽  
Apparent Influence

Late onset ataxia reported in three independently derived PrP null lines of mice has been attributed to the overexpression of the doppel protein in the CNS of these mice rather than to the loss of PrP. The central role of PrP in the transmissible spongiform encephalopathies (TSEs), the proximity of the gene which encodes doppel (Prnd) to the PrP gene (Prnp) and the structural similarity shared by PrP and doppel have led to the proposition that ataxia which develops during TSE disease could, in part, be due to doppel. In order to address this hypothesis, we have crossed our two inbred lines of PrP null mice, which either express (RCM) or do not express (NPU) the Prnd gene in the CNS, with mice expressing two Prnp a[108F189V] alleles of the PrP gene. We have found that the TSE infection does not influence the level of expression of Prnd in the CNS at the terminal stages of disease. Moreover, we have demonstrated that the level of expression of Prnd in the CNS has no influence on the incubation period, vacuolar pathology nor amount or distribution of PrPSc deposition in the brains of the TSE-infected mice. Doppel has therefore no apparent influence on the outcome of TSE disease in transgenic mice, suggesting it is unlikely to be involved in the naturally occurring TSE diseases in other species.

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.

Role of the PrP Gene in Transmissible Spongiform Encephalopathies

Intervirology ◽  
1993 ◽  
Vol 35 (1-4) ◽  
pp. 164-175 ◽  
Author(s):  
Charles Weissmann ◽  
Hansruedi Büeler ◽  
Marek Fischer ◽  
Michel Aguet
Keyword(s):  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Prp Gene

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 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.

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 Treatment of Transmissible Spongiform Encephalopathy by Intraventricular Drug Infusion in Animal Models

2004 ◽  
Vol 78 (10) ◽  
pp. 4999-5006 ◽  
Author(s):  
Katsumi Doh-ura ◽  
Kensuke Ishikawa ◽  
Ikuko Murakami-Kubo ◽  
Kensuke Sasaki ◽  
Shirou Mohri ◽  
...  
Keyword(s):  
Transmissible Spongiform Encephalopathy ◽  
Disease Stage ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Therapeutic Effects ◽  
Drug Infusion ◽  
Spongiform Encephalopathies ◽  
Significant Prolongation ◽  
Intraventricular Infusion ◽  
The Brain

ABSTRACT The therapeutic efficacy of direct drug infusion into the brain, the target organ of transmissible spongiform encephalopathies, was assessed in transgenic mice intracerebrally infected with 263K scrapie agent. Pentosan polysulfate (PPS) gave the most dramatic prolongation of the incubation period, and amphotericin B had intermediate effects, but antimalarial drugs such as quinacrine gave no significant prolongation. Treatment with the highest dose of PPS at an early or late stage of the infection prolonged the incubation time by 2.4 or 1.7 times that of the control mice, respectively. PPS infusion decreased not only abnormal prion protein deposition but also neurodegenerative changes and infectivity. These alterations were observed within the brain hemisphere fitted with an intraventricular infusion cannula but not within the contralateral hemisphere, even at the terminal disease stage long after the infusion had ended. Therapeutic effects of PPS were also demonstrated in mice infected with either RML agent or Fukuoka-1 agent. However, at doses higher than that providing the maximal effects, intraventricular PPS infusion caused adverse effects such as hematoma formation in the experimental animals. These findings indicate that intraventricular PPS infusion might be useful for the treatment of transmissible spongiform encephalopathies in humans, providing that the therapeutic dosage is carefully evaluated.

scholarly journals Spiroplasma spp. from transmissible spongiform encephalopathy brains or ticks induce spongiform encephalopathy in ruminants

2007 ◽  
Vol 56 (9) ◽  
pp. 1235-1242 ◽  
Author(s):  
Frank O. Bastian ◽  
Dearl E. Sanders ◽  
Will A. Forbes ◽  
Sue D. Hagius ◽  
Joel V. Walker ◽  
...  
Keyword(s):  
Transmissible Spongiform Encephalopathy ◽  
Clinical Signs ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Dependent Manner ◽  
Spongiform Encephalopathies ◽  
Sheep And Goats ◽  
Natural Hosts ◽  
Serological Studies ◽  
Sheep Brain

Spiroplasma, small motile wall-less bacteria, are linked by molecular and serological studies to the transmissible spongiform encephalopathies (TSEs), which include scrapie in sheep, chronic wasting disease (CWD) in deer and Creutzfeldt–Jakob disease in humans. In this study, two experiments were undertaken to determine the role of spiroplasma in the pathogenesis of TSE. In experiment 1, Spiroplasma mirum, a rabbit tick isolate that had previously been shown to experimentally induce spongiform encephalopathy in rodents, was inoculated intracranially (IC) into ruminants. S. mirum-inoculated deer manifested clinical signs of TSE after 1.5 to 5.5 months incubation. The deer, as well as sheep and goats, inoculated with S. mirum developed spongiform encephalopathy in a dose-dependent manner. In experiment 2, spiroplasma closely related to S. mirum were isolated from TSE-affected brains via passage in embryonated eggs, and propagated in cell-free M1D media. Spiroplasma spp. isolates from scrapie-affected sheep brain and from CWD-affected deer brain inoculated IC into sheep and goats induced spongiform encephalopathy closely resembling natural TSE in these animals. These data show spiroplasma to be consistently associated with TSE, and able experimentally to cause TSE in ruminant animal models, therein questioning the validity of studies that have concluded the prion, a miss-folded protease-resistant protein that builds up in TSE brains during the course of the disease, to be the sole causal agent. The spiroplasma infection models reported here will be important for investigating factors involved in the pathogenesis of TSE since ruminants are the natural hosts.

scholarly journals Evolution of transmissible spongiform encephalopathy and the prion protein gene (PRNP) in mammals

2020 ◽  
Author(s):  
Brittaney L. Buchanan ◽  
Robert M. Zink
Keyword(s):  
Marine Mammals ◽  
Phylogenetic Signal ◽  
Transmissible Spongiform Encephalopathy ◽  
Mammalian Species ◽  
Species Tree ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Wide Range ◽  
D Value

AbstractWildlife managers are concerned with transmissible spongiform encephalopathies (TSEs) as they are currently incurable, always fatal, and have the potential to cross species boundaries. Although a wide range of mammals exhibit TSEs, it is currently unclear whether they are evolutionarily clustered or if TSE+ species are randomly distributed phylogenetically. We tested whether mammalian species with TSEs are phylogenetically underdispersed on a tree derived from 102 PRNP sequences obtained from the Orthologous Mammalian Markers database. We determined that the PRNP tree was topologically congruent with a species tree for these same 102 taxa constructed from 20 aligned gene sequences, excluding the PRNP sequence. Searches in Google Scholar were done to determine whether a species is known to have expressed a TSE. TSEs were present in a variety of orders excluding Chiroptera, Eulipotyphyla, and Lagomorpha and no marine mammals (Artiodactyla) were recorded to have a TSE. We calculated the phylogenetic signal of binary traits (D-Value) to infer if the phylogenetic distribution of TSEs are conserved or dispersed. The occurrence of TSEs in both trees is non-random (Species tree D-value = 0.291; PRNP tree D-value = 0.273), and appears to have arisen independently in the recent history of different mammalian groups. Our findings suggest that the evolution of TSEs develops in groups of species irrespective of PRNP genotype. The evolution of TSEs merits continued exploration at a more in-depth phylogenetic level, as well as the search for genetic combinations that might underlie TSE diseases.

scholarly journals Ovine prion protein variant A136R154L168Q171 increases resistance to experimental challenge with bovine spongiform encephalopathy agent

2006 ◽  
Vol 87 (12) ◽  
pp. 3741-3745 ◽  
Author(s):  
Wilfred Goldmann ◽  
Fiona Houston ◽  
Paula Stewart ◽  
Matteo Perucchini ◽  
James Foster ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Protein Variant ◽  
Spongiform Encephalopathies ◽  
The Standard Model ◽  
Incubation Periods ◽  
Prp Gene ◽  
Bovine Spongiform Encephalopathy Agent ◽  
Experimental Challenge

Susceptibility and incubation periods of transmissible spongiform encephalopathies, such as scrapie in sheep, are modulated by the PrP gene. The standard model of association between ovine PrP genetics and classical scrapie susceptibility is based on PrP genotypes with respect to codons 136, 154 and 171, e.g. alanine–arginine–glutamine (ARQ). It is demonstrated here that a proline to leucine substitution in codon 168 of the ovine PrP protein gene is associated with increased resistance to experimental bovine spongiform encephalopathy (BSE) inoculation. The ARL168Q PrP allele was found in heterozygous ARP168Q/ARL168Q sheep that have so far survived intravenous BSE challenge three times longer than BSE-challenged homozygous ARP168Q/ARP168Q sheep, which develop disease in around 700 days. In contrast, the L141F polymorphism does not appear to be associated with susceptibility to intravenous BSE challenge.

scholarly journals Effectiveness of Polyene Antibiotics in Treatment of Transmissible Spongiform Encephalopathy in Transgenic Mice Expressing Syrian Hamster PrP Only in Neurons

1999 ◽  
Vol 73 (4) ◽  
pp. 3511-3513 ◽  
Author(s):  
Remi Demaimay ◽  
Richard Race ◽  
Bruce Chesebro
Keyword(s):  
Transgenic Mice ◽  
Syrian Hamster ◽  
Transmissible Spongiform Encephalopathy ◽  
Interactive Effects ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Polyene Antibiotics ◽  
Syrian Hamsters ◽  
Sites Of Action ◽  
Prp Gene

ABSTRACT To date very few drugs have favorably influenced the course of transmissible spongiform encephalopathies. In previous studies, the polyene antibiotics amphotericin B (AmB) and MS-8209 prolonged the incubation time in Syrian hamsters of the 263K strain of scrapie, but AmB had no effect against other scrapie strains in Syrian hamsters. In the present experiments using transgenic mice expressing Syrian hamster PrP in neurons only, MS-8209 extended the life spans of animals infected with the 263K strain but not the DY strain. AmB was effective against both 263K and DY and prevented death in 18% of DY-infected animals. The AmB effect against strain 263K was more prominent in mice whose endogenous PrP gene had been inactivated by homologous recombination. It was unclear whether this difference was due to a change in the duration of the disease or to possible interactive effects between the mouse PrP gene and the drugs themselves. The effectiveness of treatment after intracerebral scrapie infection in transgenic mice expressing PrP only in neurons suggested that neurons are important sites of action for these drugs.

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