Publications

forty years under the central dogma.		1998	9757833
[spongiform encephalopathies in animals and humans].	spongiform encephalopathies include several diseases of animals and humans: sheep and goat scrapie, bovine spongiform encephalopathy (bse). creutzfeldt-jakob disease (cjd) in humans and its new variant (vcjd). common characteristics of these diseases are long-term incubation, slow and progressive course, spongiform changes within nerve tissue, neuron loss and astrocytosis. causative agent responsible for spongiform encephalopathy is prion (prpsc) and it represents a posttranslationally modified ...	1998	9769654
inhibition of protease-resistant prion protein formation by porphyrins and phthalocyanines.	a central aspect of pathogenesis in the transmissible spongiform encephalopathies or prion diseases is the conversion of normal protease-sensitive prion protein (prp-sen) to the abnormal protease-resistant form, prp-res. here we identify porphyrins and phthalocyanines as inhibitors of prp-res accumulation. the most potent of these tetrapyrroles had ic50 values of 0.5-1 microm in scrapie-infected mouse neuroblastoma (scnb) cell cultures. inhibition was observed without effects on protein biosynth ...	1998	9770449
[biology of non-conventional transmissible agents or prions].	transmissible subacute spongiform encephalopathies (tse) are a group of human and animal diseases which includes creutzfeldt-jakob disease, gerstmann-straüssler-scheinker syndrome (gss), kuru, fatal familial insomnia (ffi), scrapie in sheep and goat, mink and feline transmissible encephalopathy, chronic wasting disease, and bovine spongiforme encephalopathy (bse). tse are transmissible among individuals of the same species and some of different species. these diseases stem from a specific catego ...	1998	9773035
urodynamic parameters in scrapie-affected ewes and their modifications in the course of the disease.	the aim of this study was to determine the urological abnormalities linked to spontaneous spongiform encephalopathy and their occurrence in the course of the disease. the animals used in this were 11 healthy and 20 scrapie-affected ewes. the scrapie-affected ewes were studied at a rate of once a month (1 to 5 measures; mean, 2.55) until they died. urodynamic explorations were performed. the bladder activity was explored using cystometry. the urethral activity was measured during cystometry and d ...	1998	9776019
rapid analysis of allelic variants of the sheep prp gene by oligonucleotide probes.	a rapid method to determine the allelic variants of the sheep prp gene was developed. dna samples from 128 suffolk sheep (39 rams and 89 ewes) were screened by using polymerase chain reactions and dot-blot hybridization with 32p-labeled nine allele-specific oligonucleotide probes corresponding to the polymorphic prp codons 112, 136, 154 and 171. three allelic variants of the prp gene, prp(marq), prp(tarq) and prp(marr), were found in the flocks. among those variants, nearly half of the ewes had ...	1998	9776400
prion distribution in hamster lung and brain following intraperitoneal inoculation.	prion titres were measured in the lungs and brains of syrian hamsters after intraperitoneal inoculation with sucrose gradient-purified 263k prions (approximately 10(8) ld50). prions were detected in the lung of one hamster on day 7, but were not detected in the lungs of any other hamster until day 71. prions were detected in the lungs of all hamsters sampled thereafter but titres remained low through day 127. prions were first detected in the brain on day 35 and brain titres increased exponentia ...	1998	9780064
genotyping of german sheep with respect to scrapie susceptibility.		1998	9795405
complete genomic sequence and analysis of the prion protein gene region from three mammalian species.	the prion protein (prp), first identified in scrapie-infected rodents, is encoded by a single exon of a single-copy chromosomal gene. in addition to the protein-coding exon, prp genes in mammals contain one or two 5'-noncoding exons. to learn more about the genomic organization of regions surrounding the prp exons, we sequenced 10(5) bp of dna from clones containing human, sheep, and mouse prp genes isolated in cosmids or lambda phage. our findings are as follows: (1) although the human prp tran ...	1998	9799790
severe, early and selective loss of a subpopulation of gabaergic inhibitory neurons in experimental transmissible spongiform encephalopathies.	little is known about the pathogenetic basis of characteristic symptoms in transmissible spongiform encephalopathies (tses) such as myoclonus and characteristic eeg hyperactivity. we investigated the gabaergic system and its subpopulations in mice inoculated with experimental scrapie (me7, rml, 22a strains) and creutzfeldt-jakob disease (cjd; fujisaki strain), to study damage to inhibitory neurons. since recent studies have shown electrophysiological changes in prion protein (prp) knockout mice, ...	1998	9804371
transgenic and knockout mice in research on prion diseases.	since the discovery of the prion protein (prp) gene more than a decade ago, transgenetic investigations on the prp gene have shaped the field of prion biology in an unprecedented way. many questions regarding the role of prp in susceptibility of an organism exposed to prions have been elucidated. for example mice with a targeted disruption of the prp gene have allowed the demonstration that an organism that lacks prpc is resistant to infection by prions. reconstitution of these mice with mutant ...	1998	9804380
scrapie infectivity and proteinase k-resistant prion protein in sheep placenta, brain, spleen, and lymph node: implications for transmission and antemortem diagnosis.	probable transmission of bovine spongiform encephalopathy to humans has focused intense interest on all of the transmissible spongiform encephalopathies (tses) and how they spread. in all tses, an abnormal disease-associated, proteinase k-resistant protein referred to as prp-res or prpsc accumulates in brain. in some species, prp-res accumulates in other tissues as well. sheep placenta, brain, spleen, and lymph node were analyzed in detail for prp-res and infectivity. both were detected in all b ...	1998	9806020
[prionoses--neurodegenerative diseases caused by prions, offectious proteinaceous molecules].	prionoses are a group of human and animal neurodegenerative diseases caused by prions, infectious pathogens that differ from bacteria, fungi, parasites, viroids, and viruses. despite intensive searches over the past three decades, no nucleic acid has been found within prions and considerable experimental data argue that prions are composed exclusively of proteins (glycoproteins). normal prion protein (prpc) is encoded by a gene present in all nuclear cells of humans and other mammals but is cons ...	1998	9810774
prions.	prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (prp). bovine spongiform encephalopathy (bse), scrapie of sheep, and creutzfeldt-jakob disease (cjd) of humans are among the most notable prion diseases. prions are transmissible particles that are devoid of nucleic acid and se ...	1998	9811807
the spongiform encephalopathies: prion diseases.	the spongiform encephalopathies may be caused by prions, infectious pathogens that differ from all other infectious agents in that they do not have deoxyribonucleic acid (dna) or ribonucleic acid (rna). very difficult to inactivate, they are composed of an abnormal protein. it is believed by many that prions cause sporatic and genetic neurodegenerative diseases, including scrapie and bovine spongiform encephalopathy in animals and kuru, fatal familial insomnia, creutzfeldt-jakob disease (cjd) an ...	1998	9816561
analysis of the incubation periods, induction of obesity and histopathological changes in senescence-prone and senescence-resistant mice infected with various scrapie strains.	the similarity in histopathological changes seen in scrapie-infected mice and in an uninfected senescence-accelerated mouse strain led to a study in which the mouse strain that is prone to senescence (samp8), a strain that is resistant to senescence (samr1) and a progenitor strain (akr) of these two strains were infected with three different scrapie strains, me7, 139a and 22l. for each scrapie strain, the incubation period was shortest in akr mice and longest in samr1 mice. the induction of obes ...	1998	9820164
natural occurrence of scrapie in goats in italy.		1998	9823611
a mathematical model of the dynamics of scrapie in a sheep flock.	a mathematical model is developed for the dynamics of an outbreak of scrapie in a single sheep flock with the aim of assisting the interpretation of field data. the model incorporates age structure of the sheep population, both horizontal and vertical transmission, genetic predisposition to infection, variable initial load of the infectious agent, and increasing infection load during an incubation period of the same order as sheep life expectancy. this leads to system of partial differential equ ...	1998	9825634
structural aspects of congo red as an inhibitor of protease-resistant prion protein formation.	congo red (cr) has been shown to inhibit the accumulation in scrapie-infected cells of prion protein (prp) in the abnormal protease-resistant form (prp-res). however, it was not clear if this effect was due to a direct interaction of cr with either prp-res or its protease-sensitive precursor (prp-sen) or to a less direct effect on living cells. here we show that cr inhibits prp-res formation in a simple cell-free reaction composed predominantly of purified prp-res and prp-sen. structurally modif ...	1998	9832153
molecular screening of sheep for bovine spongiform encephalopathy.	bovine spongiform encephalopathy (bse) may have transmitted to sheep through feed and pose a risk to human health. sheep bse cannot be clinically distinguished from scrapie, and conventional strain typing would be impractical on a significant scale. as human prion strains can be distinguished by differences in prion protein (prpsc) conformation and glycosylation we have applied prp(sc) typing to sheep. we found multiple western blot patterns of prp(sc) in scrapie, consistent with the known scrap ...	1998	9832197
[prions and transmissible neurodegenerative diseases].		1998	9672870
on the origins of bse.		1998	9690401
prion's progress: patterns and rates of molecular evolution in relation to spongiform disease.	modification of the cellular prion protein has been correlated with the acquisition of several neurodegenerative diseases, including kuru, scrapie, bovine spongiform encephalopathy (bse), and creutzfeldt-jakob disease (cjd). sequence conservation and amino acid identity are known to influence the efficacy of interspecific transmission. we analyzed patterns of interspecific genetic variation with a view toward identifying features related to disease transmission. the reconstructed gene trees and ...	1998	9694662
prion proteins as memory molecules: an hypothesis.	prions are infectious agents widely implicated in a variety of mammalian neurodegenerative diseases generally referred to as transmissible spongiform encephalopathies. their infectivity is primarily associated with an aberrant conformation of a host-encoded protein, the prion protein, induced by the prion itself in an autocatalytic reaction. the physiological function of this protein is not known. in this paper we suggest that alternative conformations of the prion protein, other than its pathol ...	1998	9697111
solvent extraction as an adjunct to rendering: the effect on bse and scrapie agents of hot solvents followed by dry heat and steam.	the study was designed to determine the effect on bovine spongiform encephalopathy (bse) and scrapie agents of the solvent extraction processes used in the past by british renderers. the raw material was mouse spleen infected with either the 22a strain of scrapie agent or the 301v strain of bse agent. samples were exposed to hexane, heptane, petroleum spirit or perchlorethylene at the relevant temperatures for the appropriate times. control samples were exposed to the same range of temperatures ...	1998	9698625
epidemiology and control of scrapie within a sheep flock.	mathematical models of the transmission dynamics of scrapie are used to explore the expected course of an outbreak in a sheep flock, and the potential impacts of different control measures. all models incorporate sheep demography, a long and variable scrapie incubation period, horizontal and vertical routes of transmission and genetic variation in susceptibility. outputs are compared for models which do and do not incorporate an environmental reservoir of infectivity, and which do and do not inc ...	1998	9699313
prions: properties, occurrence, modes of transmission and relevance for blood transfusion and blood derivatives.		1998	9704435
scrapie-free merino and poll dorset sheep from australia and new zealand have normal frequencies of scrapie-susceptible prp genotypes.	as natural scrapie occurs only in sheep of specific prp genotypes, one proposed aetiology was that scrapie is simply a genetic disease. however, cheviot and suffolk sheep of scrapie-susceptible genotypes are found in australia and new zealand, both generally accepted to be scrapie-free countries. a study of more common australia and new zealand sheep breeds (merinos and poll dorsets) was carried out in order to obtain more generally applicable estimates of australia and new zealand sheep prp gen ...	1998	9714260
expression of inducible nitric oxide synthase in the brains of scrapie-infected mice.	the neuronal cell damage caused by inducible nitric oxide synthase (inos) in brain has been reported to be associated, at least in part, with many neurodegenerative diseases including alzheimer's disease. we recently observed vacuolation and astrocytosis in the brains of me7 scrapie strain-infected c57bl mice. to investigate if these phenomena might have a relationship to inos, the level of inos expression was measured immunohistochemically and molecular biologically in the brains of scrapie-inf ...	1998	9718137
scrapie.	scrapie and other transmissible spongiform encephalopathies (tses) are characterized by similar pathology, biochemistry and genetics. the prp protein and its conversion to the disease-related isoform, prpsc, are crucial for the development of all tses. although scrapie is more often studied in laboratory rodents, it is not a natural disease of these animals, and much can be learned from the normal hosts, sheep. disease incidence is linked to polymorphisms and mutations of the prp gene. the compl ...	1998	9718582
structure-function aspects of prion proteins.	prions diseases are fatal neurodegenerative disorders resulting from conformational changes in the prion protein from the normal cellular form, prpc, to the infectious scrapie isoform, prpsc. high resolution structures for prpc are now available, and biochemical investigations are shedding light on the nature and determinants of the conformational transition. together, these studies are beginning to provide a framework to describe structure-function relationships of the prion protein.	1998	9720262
the importance of the disulfide bond in prion protein conversion.	the conversion of normal, protease sensitive prion protein (prp-sen) to the abnormal protease-resistant form (prp-res) is of central importance in the pathogenesis of scrapie and other transmissible spongiform encephalopathies. in the present study, the effects of reduction of the disulfide bond on the prp-sen to prp-res conversion in a cell-free system were examined. the addition of the disulfide reducing agent dithiothreitol inhibited the cell-free conversion reaction with an ic50 of 2-2.5 mm. ...	1998	9721914
polymerization of human prion peptide huprp 106-126 to amyloid in nucleic acid solution.	the human prion peptide prp106-126 polymerizes in the presence of dna both in its circular and linearized forms under solution conditions where the peptide alone does not polymerize. the polymerization process has been monitored by the increase in the fluorescence of anilino naphthalene sulfonic dye which detects the availability of the hydrophobic surface(s) in the aggregate as a consequence of polymerization. the polymerization is a nucleation dependent phenomenon as is evidenced from an exist ...	1998	9722872
polypeptide chain folding in the hydrophobic core of hamster scrapie prion: analysis by x-ray diffraction.	conversion of the noninfectious, cellular form of the scrapie prion (prpc) to the infectious form (prpsc) is thought to be driven by an alpha-helical to beta-sheet conformational transition. the n-truncated polypeptide prp27-30, which encompasses residues 90-231 of prpsc and from which the truncated peptide is derived by limited proteolysis, assembles into amyloid rods that are rich in the beta-sheet conformation. the n-terminal half of prp27-30, which includes residues 90-145 of prp (sha90-145) ...	1998	9724626
molecular analysis of bovine spongiform encephalopathy and scrapie strain variation.	five mouse scrapie strains, a mouse-passaged scrapie isolate derived from a field case in sheep in germany, and 2 mouse-passaged bovine spongiform encephalopathy (bse) isolates were analyzed by immunoblot in regards to banding patterns of proteinase k-digested pathologic prion proteins (prpres). to obtain reliable results, the photo-imager technique was used for measurement of staining band intensities. distinct and reproducible profiles were observed for the different strains or isolates. a bri ...	1998	9728537
species barrier in prion diseases: a kinetic interpretation based on the conformational adaptation of the prion protein.	prion diseases are thought to result from the conformational change of the normal cellular prion protein to a pathogenic protease-resistant isoform. however, brain extracts not containing the protease-resistant isoform of the prion protein can be infectious following interspecies transmission. the 'protein-only' hypothesis of pathogenesis is extended to provide possible explanations which could be interpreted in terms of a different infectious agent. it is proposed that normal cellular protein ( ...	1998	9729459
doubts over ability to monitor risks of bse spread to sheep.		1998	9738486
the distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy.	the administration of blood components from donors who subsequently develop creutzfeldt-jakob disease has raised the issue of blood as a possible vehicle for iatrogenic disease.	1998	9738619
mechanisms of prionsc- and hiv-1 gp120 induced neuronal cell death.	in vitro experiments revealed that the scrapie prion protein, prp(sc), as well as the prp fragment prp106-126, and the hiv-1 coat protein gp120 induce apoptosis of rat cortical neurons. the toxic effect displayed by prp and gp120 could be blocked by nmda receptor antagonists. treatment of neuronal cells with prp106-126 resulted in a drop of intracellular glutathione level and changes in the level of bcl-2. evidence is presented that gp120 causes an activation of phospholipase a2, resulting in th ...	1998	9745929
study on scrapie resistance.		1998	9746954
reversibility of scrapie inactivation is enhanced by copper.	the only known difference between the cellular (prpc) and scrapie-specific (prpsc) isoforms of the prion protein is conformational. because disruption of prpsc structure decreases scrapie infectivity, restoration of the disease-specific conformation should restore infectivity. in this study, disruption of prpsc (as monitored by the loss of proteinase k resistance) by guanidine hydrochloride (gdnhcl) resulted in decreased infectivity. upon dilution of the gdnhcl, protease resistance of prp was re ...	1998	9748215
detection and discrimination of prpsc by multi-spectral ultraviolet fluorescence.	prion diseases are progressive degenerative disorders of the central nervous system. the transmissibility and fatal nature of these diseases necessitate their rapid and accurate diagnosis. the hallmark of these diseases is the accumulation of prpsc, a protease-resistant form of a host-coded glycoprotein. we have been evaluating the use of multi-spectral ultraviolet fluorescent spectroscopy as a means of detecting and distinguishing between different forms of prpsc. spectroscopic measurements of ...	1998	9600075
a scrapie-like unfolding intermediate of the prion protein domain prp(121-231) induced by acidic ph.	the infectious agent of transmissible spongiform encephalopathies is believed to consist of an oligomeric isoform, prpsc, of the monomeric cellular prion protein, prpc. the conversion of prpc to prpsc is characterized by a decrease in alpha-helical structure, an increase in beta-sheet content, and the formation of prpsc amyloid. whereas the n-terminal part of prpc comprising residues 23-120 is flexibly disordered, its c-terminal part, prp(121-231), forms a globular domain with three alpha-helice ...	1998	9600908
concerns regarding retrospective study of reported scrapie in sheep.		1998	9604014
[transmissible spongiform encephalopathies in animals].	transmissible spongiform encephalopathies in animals are known for centuries. in particular scrapie in sheep and goats occurs worldwide; it spreads as a natural disease and is genetically controlled. chronic wasting disease (cwd) in the united states (wyoming and colorado) also spreads as natural disease among free ranging and captive elk and mule deer. in contrast, transmissible mink encephalopathy (tme) of mink in fur producing farms is caused by contaminated feed; the source of this food cont ...	1998	9611347
studies on the efficacy of hyperbaric rendering procedures in inactivating bovine spongiform encephalopathy (bse) and scrapie agents.	the efficacy of the procedures in use at the two rendering plants in the netherlands was assessed on a laboratory-scale using procedures that simulated the pressure cooking part of the rendering process. a pool of bovine spongiform encephalopathy (bse)-infected brainstem from the united kingdom and a pool of scrapie-infected brainstem from dutch sheep were used to spike the rendering materials. the mixtures were subjected to various time-temperature combinations of hyperbaric heat treatment rela ...	1998	9612912
measurement of altered aspartyl residues in the scrapie associated form of prion protein.	in transmissible spongiform encephalopathies (tse), the endogenous protease-sensitive prion protein (prp-sen) of the host is converted to a pathologic form (prp-res) that has greatly enhanced proteinase k resistance, insolubility, and beta sheet content. to investigate the possibility that alterations at aspartyl or asparaginyl residues in the form of d-aspartate and/or l-isoaspartate could play a role in either the formation or stabilization of prp-res in tse-infected animals, we assayed for th ...	1998	9618258
the distribution of scrapie-associated fibrils in neural and non-neural tissues of advanced clinical cases of natural scrapie in sheep.	the distribution of scrapie-associated fibrils (safs) throughout four brain regions, the pituitary gland, along the whole length of the spinal cord and in the sciatic nerve was assessed in 10 sheep terminally affected by scrapie and in four control sheep. tonsils, retropharyngeal, broncho-mediastinal and mesenteric lymph nodes, the distal ileum, proximal colon and spleen were also examined for fibrils in all 14 sheep. fibrils were detected in all four brain regions and throughout the length of t ...	1998	9625470
an antibody raised against a conserved sequence of the prion protein recognizes pathological isoforms in human and animal prion diseases, including creutzfeldt-jakob disease and bovine spongiform encephalopathy.	antibodies to the prion protein (prp) have been critical to the neuropathological and biochemical characterization of prp-related degenerative diseases in humans and animals. although prp is highly conserved evolutionarily, there is some sequence divergence among species; as a consequence, anti-prp antibodies have a wide spectrum of reactivity (from strong immunopositivity to lack of reactivity) when challenged with prp from diverse species. we have produced an antibody (anti-prp95-108) raised a ...	1998	9626045
complementary dna libraries and neurological disease.		1998	9626768
alterations in potassium currents may trigger neurodegeneration in murine scrapie.	conventional electrophysiological intracellular recording techniques were used to test the hypothesis that enhanced calcium entry via voltage-gated calcium channels or the n-methyl-d-aspartate (nmda) subtype of glutamate receptor-channel complex may be a primary pathological mechanism triggering neurodegeneration in scrapie and related diseases. this study was carried out at a time when cell loss is known to occur and when hippocampal pyramidal cells in area ca1 are rendered hyperexcitable follo ...	1998	9628767
descriptive epidemiology of creutzfeldt-jakob disease in six european countries, 1993-1995. eu collaborative study group for cjd.	after the occurrence of bovine spongiform encephalopathy (bse), there has been concern that transmission of bse to the human population might result in a change in the epidemiological characteristics of creutzfeldt-jakob disease (cjd). a collaborative study of cjd in the european union was performed from 1993 to 1995, to compare data from national registries for cjd in france, germany, italy, the netherlands, slovakia, and the united kingdom. five hundred seventy-five patients with definite or p ...	1998	9629846
tonsillar biopsy and prpsc detection in the preclinical diagnosis of scrapie.	preliminary findings have indicated that in naturally infected sheep, fully susceptible to scrapie (vrq-homozygous), prpsc can be detected in the tonsils approximately one year before the expected onset of clinical disease, whereas no immunostaining can be detected in animals with a semi-resistant genotype. this paper describes the technique for taking tonsillar biopsies from sheep and gives the results of the completed experiment. in another experiment prpsc was detected even earlier in compara ...	1998	9634704
determination of the frequency and distribution of vascular and parenchymal amyloid with polyclonal and n-terminal-specific prp antibodies in scrapie-affected sheep and mice.	brains from 17 histopathologically confirmed cases of scrapie, five of which had congophilic vascular amyloid, were stained immunohistochemically for prion protein (prp) using a polyclonal antibody. two clinically suspect but pathologically unconfirmed cases of natural sheep scrapie and the brains of four mice infected with the 111a murine scrapie strain were also examined. selected sections containing amyloid were stained with each of two peptide antibodies which recognise the n-terminal amino ...	1998	9637378
the use of transgenic mice in the investigation of transmissible spongiform encephalopathies.	the prion, the transmissible agent that causes spongiform encephalopathies such as scrapie, bovine spongiform encephalopathy and creutzfeldt-jakob disease, is believed to be devoid of nucleic acid and to be identical to prpsc (prion protein: scrapie form), a modified form of the normal host protein prpc (prion protein: cellular form) which is encoded by the single copy gene prnp. the 'protein only' hypothesis proposes that prpsc, when introduced into a normal host, causes the conversion of prpc ...	1998	9638817
supracriticality and the prion.		1998	9643552
guidance on the use of prp genotyping as an aid to the control of clinical scrapie. scrapie information group.		1998	9650232
neuropeptide y: some viewpoints on a multifaceted peptide in the normal and diseased nervous system.	using immunohistochemical and in situ hybridization methodologies the localization of neuropeptide tyrosine (npy) and two of its receptors, the y1- and the y2-receptor (r), has been analysed in various tissues in normal animals and animals subjected to different experimental procedures as well as animals with a genetic and an acquired disease. (1) dorsal root ganglion (drg) neurons are discussed with special focus on the effect of peripheral nerve injury. in normal drg neurons npy cannot be dete ...	1998	9651513
prions and the prion disorders.	one of us remembers sitting in a high school biology class in 1977 being taught about scrapie, a naturally occurring disorder of sheep. the teacher had no particular interest in agriculture, but was pointing out some peculiar characteristics of this disease as a biological curiosity on a wet friday afternoon. the prion disorders captured the imagination of a range of biologists (including that teacher) well before the epidemic of bovine spongiform encephalopathy (bse) and the appearance of a new ...	1998	9657843
[infectious proteins or prions. a new mechanism of disease].		1998	9658704
characterization of the human analogue of a scrapie-responsive gene.	we have recently described a novel mrna denominated scrg-1, the level of which is increased in the brains of scrapie-infected mice (dandoy-dron, f., guillo, f., benboudjema, l., deslys, j.-p., lasmézas, c., dormont, d., tovey, m. g., and dron, m. (1998) j. biol. chem. 273, 7691-7697). the increase in scrg-1 mrna in the brain follows the accumulation of prpsc, the proteinase k-resistant form of the prion protein (prp), and precedes the widespread neuronal death that occurs in late stage disease. ...	1998	9660755
role of microglia in neuronal cell death in prion disease.	to elucidate the role played by the prion protein in scrapie pathogenesis, we performed experiments with prp27-30 isolated from scrapie-infected hamster brains in cell culture and studied in vivo the temporal and spatial correlation between deposition of the disease-associated isoform of the prion protein (prpsc), microglial activation and neuronal cell death in mice infected with scrapie strains 79a, me7 and rml. the results presented here show that cellular expression of prpc and the presence ...	1998	9669696
the prion diseases.	the human prion diseases are fatal neurodegenerative maladies that may present as sporadic, genetic, or infectious illnesses. the sporadic form is called creutzfeldt-jakob disease (cjd) while the inherited disorders are called familial (f) cjd, gerstmann-straussler-scheinker (gss) disease and fatal familial insomnia (ffi). prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (prpsc). the normal, cellular prp (prpc) is conver ...	1998	9669700
comparison of scrapie-associated fibril detection and western immunoblotting for the diagnosis of natural ovine scrapie.	detergent- and proteinase k-treated extracts of grey matter were prepared from four regions of the brains of 106 sheep with scrapie, diagnosed clinically and by the demonstration of spongiform encephalopathy. the extracts were examined by electron microscopy for the presence of scrapie-associated fibrils and by western immunoblotting for the disease-specific abnormal prion protein (prpsc). as a diagnostic method, western immunoblotting proved to be more sensitive than electron microscopy, the de ...	1998	9500237
heparan sulfate proteoglycan is associated with amyloid plaques and neuroanatomically targeted prp pathology throughout the incubation period of scrapie-infected mice.	heparan sulfate proteoglycan (hspg) has been found to be associated with amyloid deposits in a number of diseases including the cerebral amyloid plaques of alzheimer's disease and the transmissible spongiform encephalopathies (tses). the role of hspg in amyloid formation and the neurodegenerative pathology of these diseases have not been established. we have addressed these questions using a scrapie mouse model which exhibits both amyloid and nonamyloid deposition of abnormal prp protein, the pr ...	1998	9500966
preliminary observations on the pathogenesis of experimental bovine spongiform encephalopathy (bse): an update.	further preliminary observations are reported of an experiment to examine the spread of infectivity and the occurrence of pathological changes in cattle exposed orally to infection with bovine spongiform encephalopathy. calves were dosed at four months of age and clinically monitored groups were killed sequentially from two to 40 months after inoculation. tissues were collected for bioassay, for histopathological examinations and for the detection of prp. previous reported observations have incl ...	1998	9501384
distribution and submicroscopic immunogold localization of cellular prion protein (prpc) in extracerebral tissues.	in transmissible spongiform encephalopathies (tse), such as scrapie in animals and creutzfeldt-jakob disease in humans, the central event is the conversion of a host-encoded amyloidogenic protein (prpc) into an abnormal isoform (prpsc) that accumulates as amyloid in tse brain. prpc is a membrane sialoglycoprotein synthesized in the central nervous system and elsewhere. we have examined the ultrastructural localization of prpc in numerous hamster and some human extracerebral tissues, by means of ...	1998	9506914
melatonin and prolactin secretion profile in naturally occurring scrapie in ewe.	the 24 hr pattern of melatonin secretion was determined in scrapie-affected ewes during the clinical course of the disease. the melatonin response to a night interruption by a 1 hr period of illumination was also measured. fourteen ewes (seven control and seven scrapie-affected ewes) were subjected to artificial short days (9l:15d). four 24 hr blood sampling sessions separated by about 10 days were performed. ewes were sacrificed when clinical signs had progressed to irreversible recumbency and ...	1998	9510437
gene expression in scrapie. cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mrna transcripts.	to define genes associated with or responsible for the neurodegenerative changes observed in transmissible spongiform encephalopathies, we analyzed gene expression in scrapie-infected mouse brain using "mrna differential display." the rna transcripts of eight genes were increased 3-8-fold in the brains of scrapie-infected animals. five of these genes have not previously been reported to exhibit increased expression in this disease: cathepsin s, the c1q b-chain of complement, apolipoprotein d, an ...	1998	9516475
cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie.	the pathogenesis of scrapie and other transmissible spongiform encephalopathies (tses) following oral uptake of agent is still poorly understood and can best be studied in mice and hamsters. the experiments described here further extend the understanding of the pathways along which infection spreads from the periphery to the brain after an oral challenge with scrapie. using tse-specific amyloid protein (tse-ap, also called prp) as a marker for infectivity, immunohistochemical evidence suggested ...	1998	9519840
effect of repeated oral infection of hamsters with scrapie.	the development of a transmissible spongiform encephalopathy upon uptake of the infectious agent in feed was studied in the model system scrapie in hamsters. compared to single dosing, repeated dosing caused disease at a considerable higher incidence. the risk of infection was higher when the time interval between repetitive dosing was short. there was a statistically significant trend of clearance of infectivity with time.	1998	9519841
characterization of the sheep apolipoprotein e (apoe) gene and allelic variations of the apoe gene in scrapie suffolk sheep.	apolipoprotein e (apoe) plays a central role in lipid transport and is suggested to be involved in neuronal repair. human apoe epsilon 4 allele is known as a risk factor for alzheimer's disease, and an association of the human apoe genotype with the human prion disease, creutzfeldt-jakob disease, is suggested, albeit controversial. we analyzed the sheep apoe gene to determine whether any association between the sheep apoe genotype and the sheep prion disease, scrapie, existed. the sheep apoe cdn ...	1998	9524247
epidemiologic analysis of reported scrapie in sheep in the united states: 1,117 cases (1947-1992)	to determine epidemiologic features associated with reported cases of scrapie in sheep in the united states.	1998	9524648
transmissible spongiform encephalopathies in food animals. human food safety and animal feed safety concerns for veterinarians.	this article presents a brief overview of transmissible spongiform encephalopathies (tses) using examples of diseases that provide evidence supporting oral transmission of the agent. agent theories are described briefly in general terms. scrapie, bovine spongiform encephalopathy (bse), chronic wasting disease, and transmissible mink encephalopathy are discussed to improve disease recognition by the food animal practitioner. control programs for scrapie and bse are described and the role of the v ...	1998	9532667
bse and hindsight.		1998	9533302
a diagnostic test for scrapie-infected sheep using a capillary electrophoresis immunoassay with fluorescent-labeled peptides.	scrapie in sheep and goats is the prototype of transmissible spongiform encephalopathies found in humans and animals. a feature of these diseases is the accumulation of rod-shaped fibrils in the brain that form from an aggregated protein. this protein (prpsc) is a protease-resistant form of a normal host cell protein. when the aggregated protein is denatured in sodium dodecyl sulfate (sds) and beta-mercaptoethanol, a monomer form of approximately 27 kda molecular mass is observed. a competition ...	1998	9551793
scrapie associated fibril detection from formaldehyde fixed brain tissue in natural cases of ovine scrapie.	the medulla oblongata of the brains of 71 scrapie-suspect cases were routinely fixed in 10 per cent formal saline and assessed for vacuolation on he-stained sections. a pool of fresh brain material was also dissected from each animal and extracts prepared for the routine detection of scrapie-associated fibrils by negative stain transmission electron microscopy. the remaining formaldehyde fixed medulla samples, which were not used for the histological examination, were coded and subjected to a pr ...	1998	9557804
expression of amino-terminally truncated prp in the mouse leading to ataxia and specific cerebellar lesions.	the physiological role of prion protein (prp) remains unknown. mice devoid of prp develop normally but are resistant to scrapie; introduction of a prp transgene restores susceptibility to the disease. to identify the regions of prp necessary for this activity, we prepared prp knockout mice expressing prps with amino-proximal deletions. surprisingly, prp lacking residues 32-121 or 32-134, but not with shorter deletions, caused severe ataxia and neuronal death limited to the granular layer of the ...	1998	9568713
synthetic peptide vaccines yield monoclonal antibodies to cellular and pathological prion proteins of ruminants.	transmissible spongiform encephalopathies are closely linked to the accumulation of a pathological isoform of a host-encoded prion protein (prp(c)), designated prp(sc). in an attempt to generate mono- and polyclonal antibodies to ruminant prp, 32 mice were vaccinated with peptide vaccines which were synthesized according to the amino acid sequence of ovine prp. by this approach five prp-reactive polyclonal antisera directed against four different domains of the protein were stimulated. splenocyt ...	1998	9568991
scrapie infectivity found in resistant species.		1998	9572135
an immunological approach to prion diseases.	ovine scrapie and bovine spongiform encephalopathy are genetic diseases, presenting probably autoimmunity transmissible by the oral route. the absence of immune response in prion diseases indicates a tolerant state for prp(c) and prp(sc). the tolerant state against these diseases should be overcome before immunizing animals. we suggest that an early diagnosis may be possible using polyclonal and monoclonal antibodies specific for either ovine or bovine prp(sc). such reagents could be obtained by ...	1998	9488187
electrophysiological properties of dorsal lateral geniculate neurons in brain slices from me7 scrapie-infected mice.	electrophysiological recordings using conventional intracellular techniques were obtained from dorsal lateral geniculate nucleus (dlgn) neurons in brain slices from me7 scrapie-infected mice at specific time points throughout the incubation period of the disease. comparisons were made with age-matched control mice. a number of dlgn neurons from control and scrapie-infected mice were injected with biocytin in order to examine their cellular morphology. mice were infected with me7 scrapie by an in ...	1998	9454635
[progress of prion theory and bovine spongiform encephalopathy].		1998	9455150
identification of the end stage of scrapie using infected neural grafts.	although the formal pathogenesis of spongiform encephalopathies has been described in detail, it is not known whether the infectious agent targets primarily neurons, glial cells, or both. to address this question, we have transplanted transgenic embryonic neural tissue overexpressing prp(c) into the forebrain of prnp -knockout mice, and infected it with scrapie prions. after infection, grafts developed severe spongiform encephalopathy. as the infected hosts were not clinically affected, we were ...	1998	9458163
the anti-prion activity of congo red. putative mechanism.	prpsc, an abnormal conformational isoform of the normal prion protein, prpc, is the only known component of the prion, a proteinacious agent that causes fatal neurodegenerative disorders in humans and other animals. the hallmark properties of prpsc are its insolubility in nondenaturing detergents and its resistance to digestion by proteases. anions such as congo red (cr) have been shown to reduce the accumulation of prpsc in a neuroblastoma cell line permanently infected with prions as well as t ...	1998	9452472
changes in the localization of brain prion proteins during scrapie infection.		1998	9443448
overexpression of nonconvertible prpc delta114-121 in scrapie-infected mouse neuroblastoma cells leads to trans-dominant inhibition of wild-type prp(sc) accumulation.	one hallmark of prion diseases is the accumulation of the abnormal isoform prp(sc) of a normal cellular glycoprotein, prpc, which is characterized by a high content of beta-sheet structures and by its partial resistance to proteinase k. it was hypothesized that the prp region comprising amino acid residues 109 to 122 [prp(109-122)], which spontaneously forms amyloid when it is synthesized as a peptide but which does not display significant secondary structure in the context of the full-length pr ...	1998	9445012
astrocytosis and proliferating cell nuclear antigen expression in brains of scrapie-infected hamsters.	scrapie is a neurodegenerative disease in sheep and goats. neuropathological examination shows astrocytosis. one issue is whether the astrocytosis seen in scrapie is a function of an increase in reactivity of individual cells, or whether there is actual replication of astrocytes. we used double-label immunohistochemistry for proliferating cell nuclear antigen (pcna) and for glial fibrillary acidic protein (gfap) to determine the mitotic state of cells and to confirm their identity as astrocytes. ...	1998	10344795
use of brain grafts to study the pathogenesis of prion diseases.	for the study of prion neurotoxicity, we used neural-grafting techniques: mice devoid of the normal host prion protein (prnp% mice) received a neural graft and were intracerebrally infected with mouse prions. the growth and differentiation properties of neural grafts were defined. growth of embryonic neuroectodermal tissue was optimal at gestational days 12.5-13.5. the blood-brain barrier is reconstituted after 7 weeks in most animals. scrapie-infected prpc-expressing grafts develop a severe spo ...	1998	10488447
extensive degeneration of catecholaminergic neurons to scrapie agent 87v in the brains of im mice.	scrapie is a degenerative disease of the central nervous system of sheep and goats. the causative agent has been passaged to a number of laboratory species, including mice and hamster. amyloid plaque formation and vacuolation, the signs of senile dementia, are found in the brains of mice infected with 87v scrapie agent. dopamine (da) and norepinephrine (ne) concentrations in the brains of scrapie-infected mice were measured with high-performance liquid chromatography-electrochemical detector (hp ...	1998	10327412
prp-dependent association of prions with splenic but not circulating lymphocytes of scrapie-infected mice.	an intact immune system, and particularly the presence of mature b lymphocytes, is crucial for mouse scrapie pathogenesis in the brain after peripheral exposure. prions are accumulated in the lymphoreticular system (lrs), but the identity of the cells containing infectivity and their role in neuroinvasion have not been determined. we show here that although prion infectivity in the spleen is associated with b and t lymphocytes and to a lesser degree with the stroma, no infectivity could be detec ...	1999	10329617
two prion-inducing regions of ure2p are nonoverlapping.	ure2p of saccharomyces cerevisiae normally functions in blocking utilization of a poor nitrogen source when a good nitrogen source is available. the non-mendelian genetic element [ure3] is a prion (infectious protein) form of ure2p, so that overexpression of ure2p induces the de novo appearance of infectious [ure3]. earlier studies defined a prion domain comprising ure2p residues 1 to 64 and a nitrogen regulation domain included in residues 66 to 354. we find that deletion of individual runs of ...	1999	10330190
a pathway for conformational diversity in proteins mediated by intramolecular chaperones.	conformational diversity within unique amino acid sequences is observed in diseases like scrapie and alzheimer's disease. the molecular basis of such diversity is unknown. similar phenomena occur in subtilisin, a serine protease homologous with eukaryotic pro-hormone convertases. the subtilisin propeptide functions as an intramolecular chaperone (imc) that imparts steric information during folding but is not required for enzymatic activity. point mutations within imcs alter folding, resulting in ...	1999	10336458
prion propagation and molecular chaperones.		1999	11194568
analytical background and discussion of the chaperone model of prion diseases.	it is generally accepted that prion infection is due solely to a protein i.e. the protein-only hypothesis. the essential constituent of infectious prions is the scrapie prion protein (prpsc) which is chemically indistinguishable from the normal, cellular protein (prpc) but exhibits distinct secondary and tertiary structure. this very unusual feature seems to be in contradiction with a major paradigm of present structural biology stated by anfinsen: a protein folds to the most stable conformation ...	1999	10855269
immunogold study of regional differences in the distribution of glucose transporter (glut-1) in mouse brain associated with physiological and accelerated aging and scrapie infection.	distribution of glucose transporter (glut-1) in brain microvascular endothelia, representing the anatomic site of the blood-brain barrier (bbb), was studied in adult, physiologically aged, senescence-accelerated prone (samp8) and in scrapie-infected mice. sections of tissue samples obtained from four brain regions (cerebral cortex, hippocampus, cerebellum, and olfactory bulb) and embedded in lowicryl k4m were exposed to anti-glut-1 antiserum followed by gold-labeled secondary antibody. labelling ...	1999	10859574
methods for studying prion protein (prp) metabolism and the formation of protease-resistant prp in cell culture and cell-free systems. an update.	transmissible spongiform encephalopathies (tse) or prion diseases result in aberrant metabolism of prion protein (prp) and the accumulation of a protease-resistant, insoluble, and possibly infectious form of prp, prp-res. studies of prp biosynthesis, intracellular trafficking, and degradation has been studied in a variety of tissue culture cells. pulse-chase metabolic labeling studies in scrapie-infected cells indicated that prp-res is made posttranslationally from an apparently normal protease- ...	1999	10934521
immunological characterization of the sheep prion protein expressed as fusion proteins in escherichia coli.	the prion protein (prp) from sheep was produced in large quantities of entire protein in escherichia coli after fusion with a carboxy-terminal hexahistidine sequence. in contrast, amino-terminal fusion with glutathione s-transferase (gst) revealed a high susceptibility toward cleavage of the protein. both recombinant proteins were recognised, at variable levels, in western blots using a panel of antibodies against the 40-56, 89-104, 98-113 and 112-115 sequences of the prion protein, similarly to ...	1999	10497869
prpc glycoform heterogeneity as a function of brain region: implications for selective targeting of neurons by prion strains.	we recently found that deletion of the asn-linked carbohydrate (cho) at residue 197 of syrian hamster (sha) prp(c) while retaining the cho at asn 181 has a profound effect on which population of neurons are targeted for conversion of shaprp(c) to shaprp(sc) in transgenic (tg) mice inoculated with scrapie prions. we hypothesized that selective targeting of neuronal populations is determined by cell-specific differences in the affinity of an infecting prp(sc) (prion) for prp(c) and that the affini ...	1999	10499442
prp gene polymorphism and natural scrapie in icelandic sheep.	the association between scrapie and polymorphism of the prion protein (prp) gene was studied in the icelandic sheep breed. polymorphism of the three codons, 136, 154 and 171, that are important for scrapie susceptibility was determined. a bsphi restriction analysis was used to study the alleles of codons 136 and 154, while density gradient gel electrophoresis (dgge) was used to analyse codon 171 and detect new polymorphisms. the prp allelic variant, vrq (amino acids at codons 136, 154 and 171), ...	1999	10501510