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advanced survival models for risk-factor analysis in scrapie.because of the confounding effects of long incubation duration and flock management, accurate epidemiological studies of scrapie outbreaks are difficult to carry out. in this study, 641 manech red-faced sheep from six scrapie-affected field flocks in pyrénées atlantiques, france, were monitored for clinical scrapie over a 6-9 year period. over this period, 170 scrapie clinical cases were recorded and half of the culled animals were submitted for post-mortem transmissible spongiform encephalopath ...200717251589
the prion strain phenomenon: molecular basis and unprecedented features.prions are unconventional infectious agents responsible for transmissible spongiform encephalopathies. compelling evidences indicate that prions are composed exclusively by a misfolded form of the prion protein (prp(sc)) that replicates in the absence of nucleic acids. one of the most challenging problems for the prion hypothesis is the existence of different strains of the infectious agent. prion strains have been characterized in most of the species. biochemical characteristics of prp(sc) used ...200717254754
microsatellites mcma53 and mcma16 on oar15 are associated with susceptibility to atypical scrapie. 200717257201
contact-induced structure transformation in transmembrane prion propagation.based on recent experimental evidences of the transmission of prion diseases due to a particular transmembrane form (termed (ctm)prp), we propose a theoretical model for the molecular mechanism of such conformational diseases, in which a misfolded (ctm)prp induces a similar misfolding of another (ctm)prp. computer simulations are performed to investigate the correlation between folding time and the concentration of misfolded prp in various processes, including dimerization, trimerization, and co ...200717259269
cells infected with scrapie and creutzfeldt-jakob disease agents produce intracellular 25-nm virus-like particles.we had repeatedly found approximately 25-nm-diameter virus-like particles in highly infectious brain fractions with little prion protein (prp), and therefore we searched for similar virus-like particles in situ in infected cell lines with high titers. neuroblastoma cells infected with the 22l strain of scrapie as well as hypothalamic gt cells infected with the fu creutzfeldt-jakob disease agent, but not parallel mock controls, displayed dense 25-nm virus-like particles in orthogonal arrays. thes ...200717267596
species-specificity of a panel of prion protein antibodies for the immunohistochemical study of animal and human prion diseases.monoclonal antibodies to the prion protein (prp) have been of critical importance in the neuropathological characterization of prp-related disease in men and animals. to determine the influence of species-specific amino-acid substitutions recognized by monoclonal antibodies, and to investigate the immunohistochemical reactivity of the latter, analyses were carried out on brain sections of cattle with bovine spongiform encephalopathy, sheep with scrapie, mice infected with scrapie, and human bein ...200717270205
reversal of misfolding: prion disease behavioral and physiological impairments recover following postnatal neuronal deletion of the prp gene.the prionoses are fatal neurodegenerative diseases caused by a pathogenic protein, prp scrapie, that derives from misfolding of a normal form, prp(c). these diseases progress through stages. a new study by mallucci et al. in this issue of neuron shows that prion disease may be reversed in mice by selective removal of the gene in neurons after early physiological, cognitive, and pathological features have developed.200717270727
identification of prion inhibitors by a fluorescence-polarization-based competitive binding assay. 200717276383
human cellular prion protein hprpc is sorted to the apical membrane of epithelial cells.propagation of the scrapie isoform of the prion protein (prp(sc)) depends on the expression of endogenous cellular prion (prp(c)). during oral infection, prp(sc) propagates, by conversion of the prp(c) to prp(sc), from the gastrointestinal tract to the nervous system. intestinal epithelium could serve as the primary site for prp(c) conversion. to investigate prp(c) sorting in epithelia cells, we have generated both a green fluorescent protein (egfp) or hemagglutinin (ha) tagged human prp(c) (hpr ...200717276393
the spread of prions through the body in naturally acquired transmissible spongiform encephalopathies.transmissible spongiform encephalopathies are fatal neurodegenerative diseases that are caused by unconventional pathogens and affect the central nervous system of animals and humans. several different forms of these diseases result from natural infection (i.e. exposure to transmissible spongiform encephalopathy agents or prions, present in the natural environment of the respective host). this holds true also for scrapie in sheep, bovine spongiform encephalopathy in cattle, chronic wasting disea ...200717288548
role of the draining lymph node in scrapie agent transmission from the skin.transmissible spongiform encephalopathies (tses) are neurodegenerative diseases that affect humans and animals. diseases include scrapie in sheep and creutzfeldt-jakob disease in humans. following peripheral exposure, tse agents usually accumulate on follicular dendritic cells (fdcs) in lymphoid tissues before neuroinvasion. studies in mice have shown that tse exposure through scarified skin is an effective means of transmission. following inoculation by this route tse agent accumulation upon fd ...200717292972
genotyping for prp gene polymorphisms in rare greek breeds of sheep. 200717293579
elevated manganese levels in blood and central nervous system occur before onset of clinical signs in scrapie and bovine spongiform encephalopathy.prion diseases, or transmissible spongiform encephalopathies, are neurodegenerative diseases that can only be accurately diagnosed by analysis of central nervous system tissue for the presence of an abnormal isoform of the prion protein known as prp(sc). furthermore, these diseases have long incubation periods during which there are no clear symptoms but where the infectious agent could still be present in the tissues. therefore, the development of diagnostic assays to detect a surrogate marker ...200717296770
clinical findings in two cases of atypical scrapie in sheep: a case report.atypical scrapie is a recently recognised form of transmissible spongiform encephalopathy of sheep that differs from classical scrapie in its neuropathological and biochemical features. most cases are detected in apparently healthy sheep and information on the clinical presentation is limited.200717298670
prpsc in salivary glands of scrapie-affected sheep.the salivary glands of scrapie-affected sheep and healthy controls were investigated for the presence of the pathological prion protein (prp(sc)). prp(sc) was detected in major (parotid and mandibular) and minor (buccal, labial, and palatine) salivary glands of naturally and experimentally infected sheep. using western blotting, the prp(sc) concentration in glands was estimated to be 0.02 to 0.005% of that in brain. immunohistochemistry revealed intracellular depositions of prp(sc) in ductal and ...200717301130
binding of n- and c-terminal anti-prion protein antibodies generates distinct phenotypes of cellular prion proteins (prpc) obtained from human, sheep, cattle and mouse.prion diseases are neurodegenerative disorders which cause creutzfeldt-jakob disease in humans, scrapie in sheep and bovine spongiform encephalopathy in cattle. the infectious agent is a protease resistant isoform (prp(sc)) of a host encoded prion protein (prp(c)). prp(sc) proteins are characterized according to size and glycoform pattern. we analyzed the glycoform patterns of prp(c) obtained from humans, sheep, cattle and mice to find interspecies variability for distinct differentiation among ...200717302739
gene expression profiling on sheep brain reveals differential transcripts in scrapie-affected/not-affected animals.this study aimed at identifying genes that could mark scrapie infection in the central nervous system of sheep. we used the subtractive suppressive hybridization (ssh) technique on brain samples from sheep healthy or clinically affected by scrapie. following subtraction, several discrete differential bands appeared between the two reciprocally subtracted samples. these bands were cloned and sequenced, allowing identifying the genes cox1, chn1, ppp2ca, lrfn5, camk2a and rabepk. two of the genes i ...200717303092
conformational diseases and structure-toxicity relationships: lessons from prion-derived peptides.the physiological form of the prion protein is normally expressed in mammalian cell and is highly conserved among species, although its role in cellular function remains elusive. available evidence suggests that this protein is essential for neuronal integrity in the brain, possibly with a role in copper metabolism and cellular response to oxidative stress. in prion diseases, the benign cellular form of the protein is converted into an insoluble, protease-resistant abnormal scrapie form. this co ...200717305562
prion infection of muscle cells in vitro.the prion agent has been detected in skeletal muscle of humans and animals with prion diseases. here we report scrapie infection of murine c2c12 myoblasts and myotubes in vitro following coculture with a scrapie-infected murine neuroblastoma (n2a) cell line but not following incubation with a scrapie-infected nonneuronal cell line or a scrapie brain homogenate. terminal differentiation of scrapie-infected c2c12 myoblasts into myotubes resulted in an increase in the expression of the disease-spec ...200717314174
quantification of peyer's patches in cheviot sheep for future scrapie pathogenesis studies.peyer's patches (pps) are the most probable sites of intestinal uptake of the transmissible spongiform encephalopathy (tse) agent. the amount of pp tissue varies considerably between different age groups of individuals, and whether this variation is related to susceptibility to tse infection raises an intriguing possibility. the purpose of this study was to determine the surface area of pp tissue and the number of associated lymphoid follicles in different age groups of neuropathogenesis unit (n ...200717320972
dynamics and genetics of prpsc placental accumulation in sheep.placentae from scrapie-affected ewes are an important source of contamination. this study confirmed that scrapie-incubating ewes bearing susceptible genotypes could produce both abnormal prion protein (prpsc)-positive and -negative placentae, depending only on the prp genotype of the fetus. the results also provided evidence indicating that scrapie-incubating arr/vrq ewes may be unable to accumulate prions in the placenta, whatever the genotype of their progeny. multinucleated trophoblast cells ...200717325381
comparison of cr36, a new heparan mimetic, and pentosan polysulfate in the treatment of prion diseases.sulfated polyanions, including pentosan polysulfate (pps) and heparan mimetics, number among the most effective drugs that have been used in experimental models of prion disease and are presumed to act in competition with endogenous heparan sulfate proteoglycans as co-receptors for prion protein (prp) on the cell surface. pps has been shown to prolong the survival of animals after intracerebral perfusion and is in limited use for the experimental treatment of human transmissible spongiform encep ...200717325382
fate of prions in soil: detergent extraction of prp from soils.the transmissible spongiform encephalopathies (tses) are caused by infectious agents whose structures have not been fully characterized but include abnormal forms of the host protein prp, designated prp(sc), which are deposited in infected tissues. the transmission routes of scrapie and chronic wasting disease (cwd) seem to include environmental spread in their epidemiology, yet the fate of tse agents in the environment is poorly understood. there are concerns that, for example, buried carcasses ...200717328187
peripheral circulation of the prion infectious agent in transgenic mice expressing the ovine prion protein gene in neurons only.for prion diseases, even if a large body of evidence indicates that both the lymphoreticular system (lrs) and peripheral nerves are involved in scrapie neuroinvasion, the processes by which prions invade the central nervous system are only partially understood.200717330790
identification of a proteinase k resistant protein for use as an internal positive control marker in prp western blotting.the routine use of an internal positive control (ipc) marker could prove useful in the diagnosis of transmissible spongiform encephalopathy (tse) diseases, particularly in surveillance programmes where large numbers of negative results are reported. detection of an endogenous ipc protein in a negative sample adds confidence to the correct sample processing throughout the analytical procedure and could avoid the reporting of false negative diagnoses. proteinase k (pk) resistance is one of the key ...200717336356
prion inactivation by the maillard reaction.since variant creutzfeldt-jakob disease (vcjd) has been suspected to be attributable to the infectious agents associated with bovine spongiform encephalopathy (bse), it is important to prevent the transmission of pathogenic forms of prion protein (prp(sc)) through contaminated feeding materials such as meat and bone meal (mbm). here, we demonstrate that the maillard reaction employing a formulation of glucose in combination with sodium hydrogen carbonates effectively reduced the infectivity (app ...200717336934
prion protein activates and fixes complement directly via the classical pathway: implications for the mechanism of scrapie agent propagation in lymphoid tissue.c1q-deficient and complement depleted mice are highly resistant to intraperitoneal scrapie infection. the molecular mechanisms of complement involvement in scrapie pathogenesis remain unclear. previous detailed studies have indicated mouse prion protein interactions with human c1q but the question of subsequent complement activation has remained unaddressed. in this investigation, murine prion protein, both recombinant and also from diseased tissue sources, directly activated and fixed complemen ...200717337056
role of the galt in scrapie agent neuroinvasion from the intestine.following oral exposure, some transmissible spongiform encephalopathy (tse) agents accumulate first upon follicular dendritic cells (fdcs) in the galt. studies in mice have shown that this accumulation is obligatory for the efficient delivery of the tse agent to the brain. however, which galts are crucial for disease pathogenesis is uncertain. mice deficient in specific galt components were used here to determine their separate involvement in scrapie agent neuroinvasion from the intestine. in th ...200717339474
prp genotypes in a pedigree flock of santa inês sheep. 200717351175
changes in the expression pattern of the nitrergic system of ovine cerebellum affected by scrapie.the constitutive and inducible isoforms of nitric oxide synthase (nos) and the end-product of nitration, nitrotyrosine, were analyzed by immunohistochemistry, western blotting, and enzymatic activity in sheep at different stages of the prion disease, scrapie. four groups were studied: 1) nonaffected (control), 2) preclinical, 3) clinical, and 4) terminal. constitutive neuronal nos (nnos) was the most abundant isoform present in cerebellar neurons of the sheep. expression of nnos increased in pre ...200717356381
scrapie strain transmission studies in ovine prp transgenic mice reveal dissimilar susceptibility.the tg(ovprp4) mouse line, expressing the sheep prion protein, is a sensitive model crucial for the identification of the bovine spongiform encephalopathy agent possibly present in natural sheep spongiform encephalopathies. it was also previously demonstrated as susceptible to infection with natural scrapie isolates from sheep harbouring various genotypes. the performance of this new transgenic mouse line in scrapie strain characterization was further assessed by intracranial inoculation of five ...200717361441
chicken antibody against a restrictive epitope of prion protein distinguishes normal and abnormal prion proteins.recently, we reported the application of a recombinant chicken igy monoclonal antibody, ab3-15, against mammalian prion protein (prp), for the diagnosis of bovine spongiform encephalopathy in cattle. in this study, we have characterized a soluble, single-chain variable fragment (scfv) form of this antibody, sphab3-15 using brain homogenates from mice. this sphab3-15 antibody recognized denatured forms of both prp(c) and prp(sc), and prp(sc) after pk-treatment, on western blotting. in sandwich el ...200717363268
differential expression of interferon responsive genes in rodent models of transmissible spongiform encephalopathy disease.the pathological hallmarks of transmissible spongiform encephalopathy (tse) diseases are the deposition of a misfolded form of a host-encoded protein (prpres), marked astrocytosis, microglial activation and spongiosis. the development of powerful gene based technologies has permitted increased levels of pro-inflammatory cytokines to be demonstrated. however, due to the use of assays of differing sensitivities and typically the analysis of a single model system it remained unclear whether this wa ...200717367538
similar biochemical signatures and prion protein genotypes in atypical scrapie and nor98 cases, france and norway.isolates of atypical scrapie recently identified in sheep and goats in france were compared with nor98 isolates reported in norway. western blot methods for characterization of the protease-resistant prion protein showed that all these isolates shared a unique biochemical signature: 5 groups of bands, including a characteristic band of apparent low molecular weight (11 kda). this pattern could originate from the presence of 3 different protease cleavage products, including the 11 kda most likely ...200717370516
polymorphisms of the prion protein gene coding region in born-after-the-reinforced-ban (barb) bovine spongiform encephalopathy cattle in great britain.polymorphisms of the prion protein gene are associated with differing susceptibilities to transmissible spongiform encephalopathy diseases, as shown for variant creutzfeldt-jakob disease in humans and scrapie in sheep, but not yet in cattle. imposition of control measures in the uk, including a reinforced ruminant feed ban in 1996, has led to a reduction in the incidence of bovine spongiform encephalopathy (bse). bse-affected cattle born after 1996 in great britain have been termed born-after-th ...200717374784
immunological differences between susceptible and resistant sheep during the preclinical phase of scrapie infection.in order to investigate the relationship between the immune response to scrapie infection and genetic susceptibility to the disease in sheep, immune cell subsets and prion protein (prp) expression were determined in susceptible and resistant suffolk sheep in the preclinical phase of infection. at 6 months of age, 12 arq/arq (susceptible) and nine arr/arr (resistant) scrapie-free suffolk lambs were challenged subcutaneously with scrapie inoculum. prefemoral lymphadenectomies were carried out at 1 ...200717374786
discriminating between cellular and misfolded prion protein by using affinity to 9-aminoacridine compounds.quinacrine and related 9-aminoacridine compounds are effective in eliminating the alternatively folded prion protein, termed prp(sc), from scrapie-infected cultured cells. clinical evaluations of quinacrine for the treatment of human prion diseases are progressing in the absence of a clear understanding of the molecular mechanism by which prion replication is blocked. here, insight into the mode of action of 9-aminoacridine compounds was sought by using a chemical proteomics approach to target i ...200717374787
cpg oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein prpsc in mice immunized with 139a scrapie-associated fibrils.prion diseases are characterized by conversion of the cellular prion protein (prp(c)) to a protease-resistant conformer, the srapie form of prp (prp(sc)). humoral immune responses to nondenatured forms of prp(sc) have never been fully characterized. we investigated whether production of antibodies to prp(sc) could occur in prp null (prnp(-/-)) mice and further, whether innate immune stimulation with the tlr9 agonist cpg oligodeoxynucleotide (odn) 1826 could enhance this process. whether such sti ...200717379700
investigation by bioassay of the efficacy of sodium hydroxide treatment on the inactivation of mouse-adapted scrapie.sodium hydroxide (naoh) has been shown to reduce the infectivity of transmissible spongiform encephalopathy (tse) agents. this study investigated the efficacy of sodium hydroxide at 0.1m, 0.25m and 0.5m concentrations for the inactivation of mouse-adapted scrapie strain me7. times and temperatures modelled conditions used in an industrial plasma fractionation plant for sanitisation of ultrafilters, and the sodium hydroxide component of clean in place sanitisation. the concentration of scrapie me ...200717074508
copper and the prion protein: methods, structures, function, and disease.the transmissible spongiform encephalopathies (tses) arise from conversion of the membrane-bound prion protein from prp(c) to prp(sc). examples of the tses include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and creutzfeldt-jakob disease in humans. although the precise function of prp(c) in healthy tissues is not known, recent research demonstrates that it binds cu(ii) in an unusual and highly conserved region of the protein termed the octarepea ...200717076634
sheep-passaged bovine spongiform encephalopathy agent exhibits altered pathobiological properties in bovine-prp transgenic mice.sheep can be experimentally infected with bovine spongiform encephalopathy (bse), and the ensuing disease is similar to scrapie in terms of pathogenesis and clinical signs. bse infection in sheep is an animal and human health concern. in this study, the transmission in boprp-tg110 mice of prions from bse-infected sheep was examined and compared to the transmission of original cattle bse in cattle and sheep scrapie prions. our results indicate no transmission barrier for sheep bse prions to infec ...200717079295
selection for scrapie resistance and simultaneous restriction of inbreeding in the rare sheep breed "mergellander".scrapie is a fatal infectious neurodegenerative disease for which susceptibility is associated with polymorphisms in the ovine prion protein (prp) gene. scrapie-eradication programmes are based on eliminating the susceptible vrq allele and/or breeding for the resistant arr allele. in rare breeds or breeds with a low frequency of the arr allele this can lead to unacceptably high inbreeding rates with associated increased risk of genetic defects and inbreeding depression. the conservation status o ...200717095110
microglial cell line established from prion protein-overexpressing mice is susceptible to various murine prion strains.several lines of evidence suggest that microglia have important roles in the pathogenesis of prion diseases. here, we establish a novel microglial cell line (mg20) from neonatal tga20 mice that overexpress murine prion protein. after exposure to chandler scrapie, we observed the replication and accumulation of disease-associated forms of the prion protein in mg20 cells up to the 15th passage. furthermore, mg20 cells were susceptible to me7, obihiro scrapie, and bovine spongiform encephalopathy a ...200717121794
atypical transmissible spongiform encephalopathies (tses) in ruminants.transmissible spongiform encephalopathies (tses) are associated with the accumulation in infected tissues of a disease-associated form of a host-encoded protein, the prion protein (prp). contrary to the normal form of the protein, this form of prp is partially resistant to protease digestion (prp(res)). detailed characterisation of prp(res) has been intensively investigated in recent years to try and decipher the diversity of tses in human and animals. this considerably and unexpectedly enlarged ...200717126958
altered prion protein glycosylation in the aging mouse brain.the normal cellular prion protein (prp(c)) is a glycoprotein with two highly conserved potential n-linked glycosylation sites. all prion diseases, whether inherited, infectious or sporadic, are believed to share the same pathogenic mechanism that is based on the conversion of the normal cellular prion protein (prp(c)) to the pathogenic scrapie prion protein (prp(sc)). however, the clinical and histopathological presentations of prion diseases are heterogeneous, depending not only on the strains ...200717144900
amino acid sequence and prion strain specific effects on the in vitro and in vivo convertibility of ovine/murine and bovine/murine prion protein chimeras.prion diseases are characterised by the conversion of a cellular prion protein (prp(c)) by its misfolded, hence pathogenic, isoform (prp(sc)). the efficiency of this transition depends on the molecular similarities between both interaction partners and on the intrinsic convertibility of prp(c). transgenic mice expressing chimeric murine/ovine prp(c) (tgmushp mice) are susceptible to bse and/or scrapie prions of bovine or ovine origin while transgenic mice expressing similar murine/bovine prp(c) ...200717145171
novel aspects of prions, their receptor molecules, and innovative approaches for tse therapy.1. prion diseases are a group of rare, fatal neurodegenerative diseases, also known as transmissible spongiform encephalopathies (tses), that affect both animals and humans and include bovine spongiform encephalopathy (bse) in cattle, scrapie in sheep, chronic wasting disease (cwd) in deer and elk, and creutzfeldt-jakob disease (cjd) in humans. tses are usually rapidly progressive and clinical symptoms comprise dementia and loss of movement coordination due to the accumulation of an abnormal iso ...200717151946
does tetracycline bind helix 2 of prion? an integrated spectroscopical and computational study of the interaction between the antibiotic and alpha helix 2 human prion protein fragments.we demonstrate here that tetracycline (tc) can strongly interact (kd' = 189 +/- 7 nm) with model peptides derived from the c-terminal globular domain of the prion protein, hprp [173-195], and that interaction concerns residues within the c-terminal half of the helix 2, a short region previously indicated as endowed with ambivalent conformational behavior and implicated in prp conversion to the beta-sheet-rich, infective scrapie variant. data have been confirmed by binding studies with the n-term ...200717152078
propagation of scrapie in peripheral nerves after footpad infection in normal and neurotoxin exposed hamsters.as is known from various animal models, the spread of agents causing transmissible spongiform encephalopathies (tse) after peripheral infection affects peripheral nerves before reaching the central nervous system (cns) and leading to a fatal end of the disease. the lack of therapeutic approaches for tse is partially due to the limited amount of information available on the involvement of host biological compartments and processes in the propagation of the infectious agent. the in vivo model pres ...200717181988
cytosolic prion protein toxicity is independent of cellular prion protein expression and prion propagation.prion diseases are transmissible neurodegenerative diseases caused by a conformational isoform of the prion protein (prp), a host-encoded cell surface sialoglycoprotein. recent evidence suggests a cytosolic fraction of prp (cyprp) functions either as an initiating factor or toxic element of prion disease. when expressed in cultured cells, cyprp acquires properties of the infectious conformation of prp (prp(sc)), including insolubility, protease resistance, aggregation, and toxicity. transgenic m ...200717182694
assessment of clinical criteria to diagnose scrapie in italy.a reliable ante-mortem test for the detection of scrapie in all genotypes has not yet been developed and clinical diagnosis remains a useful tool for surveillance purposes. this paper describes the results of a three-year study in which clinical signs consistent with scrapie were recorded according to standardized criteria in 245 sheep from 21 outbreaks in italy in order to identify helpful criteria for the diagnosis of the disease. thirty-seven sheep were scrapie-positive at post-mortem rapid t ...200716884935
from rabies to transmissible spongiform encephalopathies: an immune-mediated microbial trigger involving molecular mimicry could be the answer.the concept of experimental allergic encephalomyelitis (eae) being linked to both rabies post-vaccination encephalomyelitis and multiple sclerosis (ms) has raised the intriguing question whether animal studies carried out for the induction and transmission of transmissible spongiform encephalopathies (tses) using brain antigens including prions do have a similar immunopathogenetic mechanism. although an essential link between autoimmunity and ms has been well established, its role in the pathoge ...200716920276
the possible role of protein x, a putative auxiliary factor in pathological prion replication, in regulating a physiological endoproteolytic cleavage of cellular prion protein.the posttranslational conformational conversion of the cellular isoform of prion protein prp(c) into its scrapie isoform prp(sc) is the fundamental process underlying the pathogenesis of prion disease. based on several transgenic data, it has been postulated that a putative auxiliary factor denoted protein x functions as a molecular chaperone through its unfolding activity of prp(c) during the formation of prp(sc). however, the assumption that protein x therefore exists exclusively in prion dise ...200717008028
quantitative profiling of the pathological prion protein allotypes in bank voles by liquid chromatography-mass spectrometry.the conversion of the cellular prion protein (prp(c)) into a misfolded isoform (prp(tse)) that accumulates in the brain of affected individuals is the key feature of transmissible spongiform encephalopaties (tses). susceptibility to tses is influenced by polymorphisms of the prion gene suggesting that the presence of certain amino acid residues may facilitate the pathological conversion. in this work, we describe a quantitative, fast and reliable hplc-ms method that allowed to demonstrate that i ...200717008136
proteinase k-sensitive disease-associated ovine prion protein revealed by conformation-dependent immunoassay.prpsc [abnormal disease-specific conformation of prp (prion-related protein)] accumulates in prion-affected individuals in the form of amorphous aggregates. limited proteolysis of prpsc results in a protease-resistant core of prpsc of molecular mass of 27-30 kda (prp27-30). aggregated forms of prp co-purify with prion infectivity, although infectivity does not always correlate with the presence of prp27-30. this suggests that discrimination between prpc (normal cellular prp) and prpsc by proteol ...200717018021
a 25 nm virion is the likely cause of transmissible spongiform encephalopathies.the transmissible spongiform encephalopathies (tses) such as endemic sheep scrapie, sporadic human creutzfeldt-jakob disease (cjd), and epidemic bovine spongiform encephalopathy (bse) may all be caused by a unique class of "slow" viruses. this concept remains the most parsimonious explanation of the evidence to date, and correctly predicted the spread of the bse agent to vastly divergent species. with the popularization of the prion (infectious protein) hypothesis, substantial data pointing to a ...200717044041
detection of preclinical scrapie from serum by infrared spectroscopy and chemometrics.in this study we describe a methodology for diagnosing preclinical scrapie infection in hamsters from serum by a combination of fourier-transform infrared (ft-ir) spectroscopy and chemometrics. syrian hamsters (mesocricetus auratus) were orally inoculated with the 263k scrapie agent, or mock-infected, and sera were obtained at 70, 100 and 130 days post infection (dpi) and at the terminal stage of scrapie (160 +/- 10 dpi). the analysis of hamster sera by ft-ir spectroscopy and artificial neural n ...200717036215
association analyses between the prion protein locus and reproductive and lamb weight traits in ripollesa sheep.the objective of this study was to analyze the association between the haplotypes of the prion protein (prp) locus and several reproductive and lamb weight traits in ripollesa sheep. prion protein genotypes were available for a total of 310 sheep (7 rams, 114 ewes, and 189 lambs), all of them belonging to the purebred ripollesa flock of the universitat autònoma of barcelona, for which all sheep had a known pedigree. in addition, the genotype of 24 historical descendants of the previously genotyp ...200717060422
tse detected in a belgian arr-homozygous sheep via active surveillance.it is commonly accepted that scrapie-resistance and -susceptibility in sheep are genetically controlled. consequently, the selection of sheep with scrapie-resistant genotypes is currently one of the most important objectives of the sheep breeding associations. however, during the last two years, new data have become available on transmissible spongiform encephalopathy (tse) cases in tse-resistant sheep in several european union member states. the present paper describes the first belgian natural ...200716169265
novel polymorphisms at codons 146 and 151 in the prion protein gene of cyprus goats, and their association with natural scrapie.to discern whether an association exists between specific combinations of polymorphisms of the prion protein (prp) and natural scrapie in cyprus goats, 250 goats were examined, including 164 histologically positive cases. previously reported amino acid polymorphisms were detected at codons 154 (r-->h), 168(p-->q), 220(q-->h) and 240 (s-->p) and nucleotide alterations at codons 42 (a-->g) and 138 (c-->t). additionally, novel amino acid polymorphisms were detected at codons 146 (n-->s or d) and 15 ...200716314132
the kafkaesque approach to scrapie control--a sense of impending danger. 200716338150
molecular profiling and comparison of field transmissible spongiform encephalopathy cases diagnosed in catalunya.molecular profiling of the proteinase k resistant prion protein (prp(res)) is a technique that has been applied to the characterisation of transmissible spongiform encephalopathy (tse) strains. an interesting example of the application of this technique is the ability to differentiate, at the experimental level, between bovine spongiform encephalopathy (bse) and scrapie infection in sheep, and to distinguish between classical and atypical bse and scrapie cases. twenty-six bse cases and two scrap ...200716690334
development of recombinant chicken igy from single chain fragment of variable region for diagnosis of bse.we generated two recombinant chicken igys, designated ab3-15 and ab4-19, against mammalian prion protein (prp) from the single chain fragment of variable region (scfv) antibodies. these two antibodies recognized prp(sc) from bovine spongiform encephalopathy (bse) in cattle and were more sensitive than the corresponding scfv antibodies. these antibodies also recognized prp(sc) from other scrapie-infected mammals. these results indicate that ab3-15 and ab4-19 are useful for diagnosis of bse as wel ...200716580230
rna and cucl2 induced conformational changes of the recombinant ovine prion protein.prion diseases are a group of neurodegenerative illnesses caused by conformational conversion of benign, alpha-helix rich cellular prion protein (prp(c)) into the highly stable, beta-sheet rich scrapie prion protein (prp(sc)) isoform. to date, the role of rna on the conformational conversion of ovine prion protein in vitro remains unknown. to examine the effect of the interaction between rna and prp(c), conformations of recombinant ovine prion protein prp23-256 (ovprp23-256) binding various conc ...200716855791
simultaneous detection of eight single nucleotide polymorphisms in the ovine prion protein gene.amino acid polymorphisms in the prion protein gene (prp) affect the susceptibility of sheep to scrapie, a transmissible spongiform encephalopathy (tse). in particular, amino acid substitutions at codons 136, 154 and 171 of the ovine prp gene are associated with different degrees of susceptibility to the classical form of scrapie, caused by 'typical' scrapie strains. existing genotyping tests for scrapie susceptibility normally interrogate only the single nucleotide polymorphisms (snps) most rele ...200717590312
canadian association of neurosciences review: prion protein and prion diseases: the good and the bad.in the 1700's a strange new disease affecting sheep was recognized in europe. the disease later became known as "scrapie" and was the first of a family of similar diseases affecting a number of species that are now known as the transmissible spongiform encephalopathies (tses). the appearance of a new disease in humans linked to the consumption of meat products from infected cattle has stimulated widespread public concern and scientific interest in the prion protein and related diseases. nearly 3 ...200717598589
explaining the heterogeneous scrapie surveillance figures across europe: a meta-regression approach.two annual surveys, the abattoir and the fallen stock, monitor the presence of scrapie across europe. a simple comparison between the prevalence estimates in different countries reveals that, in 2003, the abattoir survey appears to detect more scrapie in some countries. this is contrary to evidence suggesting the greater ability of the fallen stock survey to detect the disease. we applied meta-analysis techniques to study this apparent heterogeneity in the behaviour of the surveys across europe. ...200717598881
expression of the prion protein gene (prnp) and cellular prion protein (prpc) in cattle and sheep fetuses and maternal tissues during pregnancy.we investigated the expression of prion protein gene both on mrna and protein levels in bovine and ovine female reproductive organs during gestation and various tissues of their fetuses. the fetal tissues of both species included brain, cotyledon, heart, intestine, kidney, liver, lung, and muscle. in cattle, prion protein gene (prnp) transcripts were detected by semiquantitative rt-pcr in reproductive tissues such as ovary, oviduct, endometrium, myometrium, follicles, and granulosa cells. in var ...200717605301
susceptibility of cattle to first-passage intracerebral inoculation with chronic wasting disease agent from white-tailed deer.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 cal ...200717606510
discrimination of sheep susceptible and resistant to transmissible spongiform encephalopathies by an haplotype specific monoclonal antibody.in the present report, the selective detection of sheep prp haplotypes by monoclonal antibody 2a11 is described. it is showed that the substitution of glutamine by arginine but not by histidine at ovine prp position 171 abolishes completely the recognition of either prp(c) or prp(d) by mab 2a11, in such a way that the application of this antibody allows the unambiguous discrimination of r(171) homozygotes. on the basis of the high resistance to classical scrapie and bovine spongiform encephaloph ...200717614145
alteration of iron regulatory proteins (irp1 and irp2) and ferritin in the brains of scrapie-infected mice.considerable evidence suggests that oxidative stress may be involved in the pathogenesis of transmissible spongiform encephalopathies (tses). to investigate the involvement of iron metabolism in tses, we examined the expression levels of iron regulatory proteins (irps), ferritins, and binding activities of irps to iron-responsive element (ire) in scrapie-infected mice. we found that the irps-ire-binding activities and ferritins were increased in the astrocytes of hippocampus and cerebral cortex ...200717614197
hot spots in prion protein for pathogenic conversion.prion proteins are key molecules in transmissible spongiform encephalopathies (tses), but the precise mechanism of the conversion from the cellular form (prp(c)) to the scrapie form (prp(sc)) is still unknown. here we discovered a chemical chaperone to stabilize the prp(c) conformation and identified the hot spots to stop the pathogenic conversion. we conducted in silico screening to find compounds that fitted into a "pocket" created by residues undergoing the conformational rearrangements betwe ...200717616582
classical sheep transmissible spongiform encephalopathies: pathogenesis, pathological phenotypes and clinical disease.scrapie is a prion disease or transmissible spongiform encephalopathy (tse) of sheep, goats and moufflon. as with its human counterparts, pathology consists of vacuolation, gliosis and accumulations of abnormal forms of a host prion protein (prpd) in the brain of affected individuals. immunohistochemical methods can be used to identify both the intracellular truncation sites of prpd in different cell types (prpd epitope mapping) and the different morphological patterns of accumulation (prpd prof ...200717617870
disease-specific particles without prion protein in prion diseases - phenomenon or epiphenomenon?the search for the cause of transmissible spongiform encephalopathies (tses) has a long and tortuous history. in a recent paper, 25-nm virus-like particles were identified that were consistently observed in cell cultures infected with creutzfeldt-jakob disease (cjd) and scrapie; they are similar to, or even identical with, the virus-like tubulovesicular structures (tvs) found in experimental scrapie as early as in 1968, and subsequently in all naturally occurring and experimentally induced tses. ...200717617871
immunohistochemistry for prpsc in natural scrapie reveals patterns which are associated with the prp genotype.immunohistochemistry for prpsc is used widely in scrapie diagnosis. in natural scrapie cases the use of immunohistochemistry (ihc) has revealed the existence of up to 12 different morphological types of immunostained deposits. the significance of this pattern variability in relation to genotype has not been studied extensively in natural disease. in this study we recorded in detail prpsc patterns at the obex level of the medulla oblongata from 163 animals derived from 55 flocks which presented t ...200717617872
oral scrapie infection modifies the homeostasis of peyer's patches' dendritic cells.in transmitted prion diseases the immune system supports the replication and the propagation of the pathogenic agent (prpsc). dcs, which are mobile cells present in large numbers within lymph organs, are suspected to carry prions through the lymphoid system and to transfer them towards the peripheral nervous system. in this study, c57bl/6 mice were orally inoculated with prpsc (scrapie strain 139a) and sacrificed at the preclinical stages of the disease. immunolabelled cryosections of peyer's pa ...200717622551
experimental scrapie in 'plt' mice: an assessment of the role of dendritic-cell migration in the pathogenesis of prion diseases.peripherally acquired transmissible spongiform encephalopathies display strikingly long incubation periods, during which increasing amounts of prions can be detected in lymphoid tissues. while precise sites of peripheral accumulation have been described, the mechanisms of prion transport from mucosa and skin to lymphoid and nervous tissues remain unknown. because of unique functional abilities, dendritic cells (dcs) have been suspected to participate in prion pathogenesis. in mice inoculated sub ...200717622642
fatal neurological disease in scrapie-infected mice induced for experimental autoimmune encephalomyelitis.during the years or decades of prion disease incubation, at-risk individuals are certain to encounter diverse pathological insults, such as viral and bacterial infections, autoimmune diseases, or inflammatory processes. whether prion disease incubation time and clinical signs or otherwise the pathology of intercurrent diseases can be affected by the coinfection process is unknown. to investigate this possibility, mice infected with the scrapie agent at both high and low titers were subsequently ...200717626090
prpc does not mediate internalization of prpsc but is required at an early stage for de novo prion infection of rov cells.we have studied the interactions of exogenous prions with an epithelial cell line inducibly expressing prpc protein and permissive to infection by a sheep scrapie agent. we demonstrate that abnormal prp (prpsc) and prion infectivity are efficiently internalized in rov cells, whether or not prpc is expressed. at odds with earlier studies implicating cellular heparan sulfates in prpsc internalization, we failed to find any involvement of such molecules in rov cells, indicating that prions can ente ...200717626095
is vaccination against transmissible spongiform encephalopathy feasible?prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformation change of the cellular form of a normal, self-protein called a prion protein (prp(c) [c for cellular]) to a pathological and infectious conformation known as scrapie form (prpsc [sc for scrapie]). currently, all prion diseases are without effective treatment and are universally fatal. the emergence of bovine spongiform encephalopathy and variant creut ...200717633306
cellular prion protein (prpc) protects neuronal cells from the effect of huntingtin aggregation.the effect of normal cellular prion protein (prp(c)) on abnormal protein aggregation was examined by transfecting huntingtin fragments (htt) into sn56 neuronal-derived cells depleted of prp(c) by rna interference. prp(c) depletion caused an increase in both the number of cells containing granules and the number of apoptotic cells. consistent with the increase in htt aggregation, prp(c) depletion caused an decrease in proteasome activity and a decrease in the activities of cellular defense enzyme ...200717635996
investigations of a prion infectivity assay to evaluate methods of decontamination.prions are unique infectious agents which have been shown to be transmitted iatrogenically through contaminated surfaces. surface contamination is a concern on reusable medical devices and various industrial surfaces, but there is currently no standard, accepted model to evaluate surface prion decontamination. in this report, a set of both in vitro and in vivo methods were investigated based on the contamination of surface through artificial exposure to infected brain. an in vitro surface contam ...200717640752
ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein.the scrapie prion protein isoform, prpsc, is a prion-associated marker that seeds the conformational conversion and polymerization of normal protease-sensitive prion protein (prp-sen). this seeding activity allows ultrasensitive detection of prpsc using cyclical sonicated amplification (pmca) reactions and brain homogenate as a source of prp-sen. here we describe a much faster seeded polymerization method (rprp-pmca) which detects >or=50 ag of hamster prpsc (approximately 0.003 lethal dose) with ...200717643109
exposure of sheep scrapie brain homogenate to rumen-simulating conditions does not result in a reduction of prp(sc) levels.experiments were designed to evaluate the potential of rumen-simulating conditions to reduce prp(sc) levels.200717576225
insights into prion strains and neurotoxicity.transmissible spongiform encephalopathies (tses) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. it is now widely accepted that the infectious agent that causes tses is prp(sc), an aggregated moiety of the host-derived membrane glycolipoprotein prp(c). although prp(c) is encoded by the host genome, prions themselves encipher many phenotypic tse variants, known as prion strains. prion strains are tse isolates that, after inoculation into distinc ...200717585315
epidemiological and genetical differences between classical and atypical scrapie cases.the aim of this study was to analyze the epidemiology and prion protein (prp) genetics in scrapie-affected sheep flocks in germany. for this purpose, 224 german scrapie cases in sheep diagnosed between january 2002 and february 2006 were classified as classical or atypical scrapie and the amino acids at codons 136, 141, 154 and 171 were determined. likewise, representative numbers of flock mates were genotyped. significant epidemiological differences were observed between classical and atypical ...200717156738
evidence for degradation of abnormal prion protein in tissues from sheep with scrapie during composting.this study investigated whether the abnormal prion protein (prp(sc)) in tissues from sheep with scrapie would be destroyed by composting. tissues from sheep naturally infected with scrapie were placed within fiberglass mesh bags and buried in compost piles for 108 d in experiment 1 or 148 d in experiment 2. the temperature in the compost piles rose quickly; it was above 60 degrees c for about 2 wk and then slowly declined to the ambient temperature. before composting, prpsc was detected in all t ...200717193880
the vagus nerve as a conduit for neuroinvasion, a diagnostic tool, and a therapeutic pathway for transmissible spongiform encephalopathies, including variant creutzfeld jacob disease.it is hypothesised that the vagus nerve (cranial nerve x) is an important conduit for infective neuroinvasion during the incubation of certain transmissible spongiform encephalopathies (tses) including scrapie in sheep, variant creutzfeld jacob disease in humans, chronic wasting disease in deer, and bovine spongiform encephalopathy in cattle. presence of infection in the brainstem will disrupt normal function of this important region responsible for autonomic control of visceral function via the ...200717166667
efficient in vitro amplification of a mouse-adapted scrapie prion protein.protein misfolding cyclic amplification (pmca) is a highly sensitive technique used to detect minute amounts of scrapie prion protein (prp(sc)), a major protein component of the infectious agents associated with prion diseases. although exponential in vitro amplification of hamster scrapie prp(sc) has been established, the pmca used was unsuccessful in achieving good amplification of prp(sc) from other animals. here, we have investigated the cause of the insufficient prp(sc) amplification in mic ...200717174030
prion infection-impaired functional blocks identified by proteomics enlighten the targets and the curing pathways of an anti-prion drug.prion-induced neurodegeneration results from multiple cellular alterations among which the accumulation of a modified form of the host protein prp is but a hallmark. drug treatments need understanding of underlying mechanisms. proteomics allows getting a comprehensive view of perturbations leading to neuronal death. heparan sulfate mimetics has proved to be efficient to clear scrapie protein in cultured cells and in animals. to investigate the mechanisms of drug attack, protein profiles of the n ...200717174161
cellular prion protein signaling in serotonergic neuronal cells.the cellular prion protein prp(c) is the normal counterpart of the scrapie prion protein prp(sc), the main component of the infectious agent of transmissible spongiform encephalopathies (tses). it is a ubiquitous cell-surface glycoprotein, abundantly expressed in neurons, which constitute the targets of tse pathogenesis. taking advantage of the 1c11 neuroectodermal cell line, endowed with the capacity to convert into 1c11(5-ht) serotonergic or 1c11(ne) noradrenergic neuronal cells, allowed us to ...200717405922
prevention of prion propagation by dehydrocholesterol reductase inhibitors in cultured cells and a therapeutic trial in mice.in prion diseases, the normal cellular form of prion protein (prp(c)) is converted into the disease-associated isoforms (prp(sc)) which accumulate in the infected tissues. although the precise mechanism of this conversion remains unsolved, drugs of various categories have been reported to reduce the accumulation of prp(sc) in prion-infected cultured cells. we here show that ay-9944 (a 7-dehydrocholesterol reductase inhibitor) and u18666a (a 24-dehydrocholesterol reductase inhibitor) prevent prp( ...200717409533
could a virus contribute to weight gain?obesity is a serious public health problem associated with increased morbidity and mortality. although the causes for obesity are unclear, it seems that environmental, genetic, neural and endocrine factors contribute to its development. however, the rapid global spread of obesity resembles epidemiologically the spread of an infectious disease. thus far, little consideration has been given to the possibility that the epidemic of obesity could be due to an infectious agent. seven viruses and a scr ...200717420782
infectobesity: obesity of infectious origin.the rapid increase in obesity and the associated health care costs have prompted a search for better approaches for its prevention and management. such efforts may be facilitated by better understanding the etiology of obesity. of the several etiological factors, infection, an unusual causative factor, has recently started receiving greater attention. in the last two decades, 10 adipogenic pathogens were reported, including human and nonhuman viruses, scrapie agents, bacteria, and gut microflora ...200717425944
which prp haplotypes in a french sheep population are the most susceptible to atypical scrapie?a french sheep case control study has been organised to estimate the effects of the prp haplotypes on resistance to atypical scrapie. the alhq and afrq haplotypes are significantly more susceptible than the others.200717426916
mapping of possible prion protein self-interaction domains using peptide arrays.the common event in transmissible spongiform encephalopathies (tses) or prion diseases is the conversion of host-encoded protease sensitive cellular prion protein (prpc) into strain dependent isoforms of scrapie associated protease resistant isoform (prpsc) of prion protein (prp). these processes are determined by similarities as well as strain dependent variations in the prp structure. selective self-interaction between prp molecules is the most probable basis for initiation of these processes, ...200717430579
use of thermolysin in the diagnosis of prion diseases.the molecular diagnosis of prion diseases almost always involves the use of a protease to distinguish prpc from prpsc and invariably the protease of choice is proteinase k. here, we have applied the protease thermolysin to the diagnosis of animal prion diseases. this thermostable protease cleaves at the hydrophobic residues leu, ile, phe, val, ala, and met, residues that are absent from the protease accessible aminoterminal region of prpsc. therefore, although thermolysin readily digests prpc in ...200717435282
transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model.to identify the dynamic transcriptional alterations in cns during the development of prion disease, brains of scrapie-infected mice and age-matched, mock-inoculated controls were analyzed immediately before inoculation and at different time points post-inoculation using affymetrix microarray technique. a total of 449 probe sets, representing 430 genes, showed differential expression between scrapie- and mock-inoculated mice over the time course. these genes could be separated into two clusters a ...200717437544
prophylactic effect of dietary seaweed fucoidan against enteral prion infection.dietary seaweed fucoidan delays the onset of disease of enterally infected mice with scrapie when given orally for 6 days after infection, but not when given before the infection. this effect was not modified at a tested fucoidan dose range and appeared to reach the maximum level at a concentration of 2.5% or less in feed. daily uptake of fucoidan might be prophylactic against prion diseases caused by ingestion of prion-contaminated materials, although further evaluation of its pharmacology rema ...200717438058
adsorption of pathogenic prion protein to quartz sand.management responses to prion diseases of cattle, deer, and elk create a significant need for safe and effective disposal of infected carcasses and other materials. furthermore, soil may contribute to the horizontal transmission of sheep scrapie and cervid chronic wasting disease by serving as an environmental reservoirforthe infectious agent. as an initial step toward understanding prion mobility in porous materials such as soil and landfilled waste, the influence of ph and ionic strength (l) o ...200717438782
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