Progress on low susceptibility mechanisms of transmissible spongiform encephalopathies.
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ABSTRACT:
SUBMITTER: Qing LL
PROVIDER: S-EPMC4790361 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
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Progress on low susceptibility mechanisms of transmissible spongiform encephalopathies.
Qing Li-Li LL Zhao Hui H Liu Lin-Lin LL
Dong wu xue yan jiu = Zoological research 20140901 5
Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative diseases detected in a wide range of mammalian species. The "protein-only" hypothesis of TSE suggests that prions are transmissible particles devoid of nucleic acid and the primary pathogenic event is thought to be the conversion of cellular prion protein (PrP(C)) into the disease-associated isoform (PrP(Sc)). According to susceptibility to TSEs, animals can be classified into s ...[more]
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Project description:BackgroundAs there is limited information about the clinical signs of BSE and scrapie in goats, studies were conducted to describe the clinical progression of scrapie and BSE in goats and to evaluate a short clinical protocol for its use in detecting scrapie-affected goats in two herds with previously confirmed scrapie cases. Clinical assessments were carried out in five goats intracerebrally infected with the BSE agent as well as five reported scrapie suspects and 346 goats subject to cull from the two herds, 24 of which were retained for further monitoring. The brain and selected lymphoid tissue were examined by postmortem tests for disease confirmation.ResultsThe sensitivity and specificity of the short clinical protocol in detecting a scrapie case in the scrapie-affected herds was 3.9% and 99.6%, respectively, based on the presence of tremor, positive scratch test, extensive hair loss, ataxia and absent menace response. All BSE- and scrapie-affected goats displayed abnormalities in sensation (over-reactivity to external stimuli, startle responses, pruritus, absent menace response) and movement (ataxia, tremor, postural deficits) at an advanced clinical stage but the first detectable sign associated with scrapie or BSE could vary between animals. Signs of pruritus were not always present despite similar prion protein genotypes. Clinical signs of scrapie were also displayed by two scrapie cases that presented with detectable disease-associated prion protein only in lymphoid tissues.ConclusionsBSE and scrapie may present as pruritic and non-pruritic forms in goats. Signs assessed for the clinical diagnosis of scrapie or BSE in goats should include postural and gait abnormalities, pruritus and visual impairment. However, many scrapie cases will be missed if detection is solely based on the display of clinical signs. PrPd accumulation in the brain appeared to be related to the severity of clinical disease but not to the display of individual neurological signs.
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Project description:Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, arise from the structural conversion of the monomeric, cellular prion protein (PrPC) into its multimeric scrapie form (PrPSc). These pathologies comprise a group of intractable, rapidly evolving neurodegenerative diseases. Currently, a definitive diagnosis of TSE relies on the detection of PrPSc and/or the identification of pathognomonic histological features in brain tissue samples, which are usually obtained postmortem or, in rare cases, by brain biopsy (antemortem). Over the past two decades, several paraclinical tests for antemortem diagnosis have been developed to preclude the need for brain samples. Some of these alternative methods have been validated and can provide a probable diagnosis when combined with clinical evaluation. Paraclinical tests include in vitro cell-free conversion techniques, such as the real-time quaking-induced conversion (RT-QuIC), as well as immunoassays, electroencephalography (EEG), and brain bioimaging methods, such as magnetic resonance imaging (MRI), whose importance has increased over the years. PrPSc is the main biomarker in TSEs, and the RT-QuIC assay stands out for its ability to detect PrPSc in cerebrospinal fluid (CSF), olfactory mucosa, and dermatome skin samples with high sensitivity and specificity. Other biochemical biomarkers are the proteins 14-3-3, tau, neuron-specific enolase (NSE), astroglial protein S100B, α-synuclein, and neurofilament light chain protein (NFL), but they are not specific for TSEs. This paper reviews the techniques employed for definite diagnosis, as well as the clinical and paraclinical methods for possible and probable diagnosis, both those in use currently and those no longer employed. We also discuss current criteria, challenges, and perspectives for TSE diagnosis. An early and accurate diagnosis may allow earlier implementation of strategies to delay or stop disease progression.
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Project description:Transmissible spongiform encephalopathies are incurable neurodegenerative diseases, associated with the conversion of the physiological prion protein to its disease-associated counterpart. Even though immunization against transmissible spongiform encephalopathies has shown great potential, immune tolerance effects impede the use of active immunization protocols for successful prophylaxis. In this study, we evaluate the use of trypanosomes as biological platforms for the presentation of a prion antigenic peptide to the host immune system. Using the engineered trypanosomes in an immunization protocol without the use of adjuvants led to the development of a humoral immune response against the prion protein in wild type mice, without the appearance of adverse reactions. The immune reaction elicited with this protocol displayed in vitro therapeutic potential and was further evaluated in a bioassay where immunized mice were partially protected in a representative murine model of prion diseases. Further studies are underway to better characterize the immune reaction and optimize the immunization protocol.
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Project description:Scrapie is a naturally occurring transmissible spongiform encephalopathy of sheep and goats. This fatal neurodegenerative disease is caused by misfolding of the cellular prion protein to pathogenic β-rich conformers (PrPSc) that accumulate in higher order structures of the brain and other tissues. This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions and for strain discrimination in a variety of biological tissues from humans and animals. In this study, we evaluated how PrPSc isolated from sheep of different genotypes after inoculation with the scrapie agent influence the fibril formation in vitro using RT-QuIC. We found that reaction mixtures seeded with PrPSc from genotype VRQ/VRQ sheep brains have better conversion efficiency with 132M elk substrate compared to reactions seeded with PrPSc from the brains of sheep with the ARQ/ARQ genotype no matter which strain of scrapie was used to seed the reactions. We also inoculated transgenic mice expressing 132M elk PRNP (Tg12) with the scrapie agent from different genotypes of sheep to compare with our RT-QuIC results. The bioassays support the data showing a significantly shorter incubation period for inoculum from VRQ/VRQ sheep when compared to inoculum from ARQ/ARQ sheep. Thus, we conclude that the genotype of both source and recipient can strongly influence transmission.
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Project description:Naturally occurring transmissible spongiform encephalopathies (TSEs) accumulate disease-specific forms of prion protein on cell membranes in association with pathognomonic lesions. We wished to determine whether synthetic prion protein disorders recapitulated these and other subcellular TSE-specific changes.SSLOW is a TSE initiated with refolded synthetic prion protein. Five terminally sick hamsters previously intracerebrally inoculated with third passage SSLOW were examined using light and immunogold electron microscopy.SSLOW-affected hamsters showed widespread abnormal prion protein (PrP(SSLOW) ) and amyloid plaques. PrP(SSLOW) accumulated on plasma lemmas of neurites and glia without pathological changes. PrP(SSLOW) also colocalized with increased coated vesicles and pits, coated spiral membrane invaginations and membrane microfolding. PrP(SSLOW) was additionally observed in lysosomes of microglial cells but not of neurones or astrocytes.PrP(SSLOW) is propagated by cell membrane conversion of normal PrP and lethal disease may be linked to the progressive growth of amyloid plaques. Cell membrane changes present in SSLOW are indistinguishable from those of naturally occurring TSEs. However, some lesions found in SSLOW are absent in natural animal TSEs and vice versa. SSLOW may not entirely recapitulate neuropathological features previously described for natural disease. End-stage neuropathology in SSLOW, particularly the nature and distribution of amyloid plaques may be significantly influenced by the early redistribution of seeds within the inoculum and its recirculation following interstitial, perivascular and other drainage pathways. The way in which seeds are distributed and aggregate into plaques in SSLOW has significant overlap with murine APP overexpressing mice challenged with A?.
| S-EPMC3783560 | biostudies-literature
Project description:Protein misfolding, protein aggregation and disruption to cellular proteostasis are key processes in the propagation of disease and, in some progressive neurodegenerative diseases of the central nervous system, the misfolded protein can act as a self-replicating template or prion converting its normal isoform into a misfolded copy of itself. We have investigated the sheep transmissible spongiform encephalopathy, scrapie, and developed a multiple selected reaction monitoring (mSRM) mass spectrometry assay to quantify brain peptides representing the "ragged" N-terminus and the core of ovine prion protein (PrP(Sc)) by using Q-Tof mass spectrometry. This allowed us to identify pyroglutamylated N-terminal fragments of PrP(Sc) at residues 86, 95 and 101, and establish that these fragments were likely to be the result of in vivo processes. We found that the ratios of pyroglutamylated PrP(Sc) fragments were different in sheep of different breeds and geographical origin, and our expanded ovine PrP(Sc) assay was able to determine the ratio and allotypes of PrP accumulating in diseased brain of PrP heterozygous sheep; it also revealed significant differences between N-terminal amino acid profiles (N-TAAPs) in other types of ovine prion disease, CH1641 scrapie and ovine BSE. Variable rates of PrP misfolding, aggregation and degradation are the likely basis for phenotypic (or strain) differences in prion-affected animals and our mass spectrometry-based approach allows the simultaneous investigation of factors such as post-translational modification (pyroglutamyl formation), conformation (by N-TAAP analysis) and amino-acid polymorphisms (allotype ratio) which affect the kinetics of these proteostatic processes.
| S-EPMC4429639 | biostudies-literature
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Project description:BackgroundThe purpose of this study is to analyse the trends in scientific research on transmissible spongiform encephalopathies by applying bibliometric tools to the scientific literature published between 1973 and 2002.MethodsThe data for the study were obtained from Medline database, in order to determine the volume of scientific output in the above period, the countries involved, the type of document and the trends in the subject matters addressed. The period 1973-2002 was divided in three sub-periods.ResultsWe observed a significant growth in scientific production. The percentage of increase is 871.7 from 1973 to 2002. This is more evident since 1991 and particularly in the 1996-2001 period. The countries found to have the highest output were the United States, the United Kingdom, Japan, France and Germany. The evolution in the subject matters was almost constant in the three sub-periods in which the study was divided. In the first and second sub-periods, the subject matters of greatest interest were more general, i.e Nervous system or Nervous system diseases, Creutzfeldt-Jakob disease, Scrapie, and Chemicals and Drugs, but in the last sub-period, some changes were observed because the Prion-related matters had the greatest presence. Collaboration among authors is small from 1973 to 1992, but increases notably in the third sub-period, and also the number of authors and clusters formed. Some of the authors, like Gajdusek or Prusiner, appear in the whole period.ConclusionThe study reveals a very high increase in scientific production. It is related also with the beginnings of research on bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease, with the establishment of progressive collaboration relationships and a reflection of public health concerns about this problem.
| S-EPMC1615877 | biostudies-literature
Project description:This report presents the results of surveillance on transmissible spongiform encephalopathies (TSE) in bovine animals, sheep, goats, cervids and other species, and genotyping in sheep, carried out in 2018 by 28 Member States (MS) according to legislation, and by Iceland, North Macedonia, Norway and Switzerland (non-MS). In total, 1,181,934 cattle were tested by MS, a 10% decrease from 2017 and 20,402 by the four non-MS. One case of classical bovine spongiform encephalopathy (BSE) was reported in 2018 by the UK, born after the enforcement of the total feed ban. Three atypical BSE cases (2 L-type/1 H-type) were reported by France. Over the year, a total of 325,386 sheep and 138,128 goats were tested in the EU, an increase of 3.4% and 17.8%, respectively, compared to 2017. In sheep, 934 cases of scrapie were reported: 821 classical (99 index cases and 97.8% with genotypes of susceptible groups) by 7 MS and 113 atypical (105 index cases) by 14 MS. Twenty-nine ovine scrapie cases were reported by Iceland and Norway. Random genotyping was only reported by eight MS and after excluding Cyprus showed that 18.7% of the genotyped sheep carried genotypes of the susceptible groups. In goats, 523 cases of scrapie were reported: 517 classical (38 index cases) by seven MS and six atypical (all index cases) by four MS. The heterogenous enforcement of a 3-year surveillance programme for chronic wasting disease (CWD) from 1/1/2018 in six MS (Estonia, Finland, Latvia, Lithuania, Poland and Sweden) resulted in the testing of 5,110 cervids and the confirmation of the first case of CWD in the EU: a wild moose in Finland. Other six MS tested 3,075 cervids with no positive results. Norway tested 33,037 cervids in 2018, resulting in seven new cases: six reindeer and one moose. In total, 105 animals from three other species were tested by two MS, with negative results.
| S-EPMC7008828 | biostudies-literature
Project description:This report presents the results of surveillance on transmissible spongiform encephalopathies (TSEs) in bovine animals, sheep, goats, cervids and other animal species, as well as genotyping in sheep, carried out in 2017 in the European Union (EU) according to Regulation (EC) 999/2001, and in Iceland, Norway and Switzerland. In total, 1,312,714 cattle were tested by the 28 EU Member States (MSs) which is a decrease of 3% compared with 2016; 18,526 were tested by the three non-MSs. For the first time since bovine spongiform encephalopathy (BSE) has been reported, no cases of classical BSE were reported in 2017. Six atypical BSE cases were reported by three different MSs: Spain 1 H-BSE/2 L-BSE; France 1 H-BSE/1 L-BSE; and Ireland 1 L-BSE. Over the year, 314,547 sheep and 117,268 goats were tested in the EU. In sheep, 933 cases of scrapie were reported: 839 classical and unknown (145 index cases) by eight MSs and 94 atypical (89 index cases) by 13 MSs. Fourteen ovine scrapie cases were reported by Iceland and Norway. Of all classical scrapie cases, 98.2% occurred in sheep with genotypes of susceptible groups. The genotyping of a random sample in 21 MSs showed that 26.5% of the genotyped sheep carried genotypes of the susceptible groups. In goats 567 cases of scrapie were reported: 558 classical (42 index cases) by seven MSs and nine atypical (seven index cases) by five MSs. In total, 3,585 cervids were tested for TSE by ten MSs, mostly by Romania. All results were negative. Eleven cases of chronic wasting disease (CWD) cases were reported in cervids by Norway: nine wild reindeer, one moose and, for the first time ever, one red deer. In total, 185 animals from five species other than cattle, small ruminants and cervids were tested by three MSs, with negative results.
| S-EPMC7009765 | biostudies-literature