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Spongiform Encephalopathy (spongiform + encephalopathy)
Kinds of Spongiform Encephalopathy Selected AbstractsInformation, labelling, and vertical coordination: an analysis of the Italian meat supply networksAGRIBUSINESS : AN INTERNATIONAL JOURNAL, Issue 3 2008Alessandro Banterle After the Bovine Spongiform Encephalopathy (BSE) crisis, the European Union (EU) introduced mandatory and voluntary labelling for meat products to reduce the food safety concerns of consumers and to ensure a better distribution of liability among agents of the meat supply chain. The purpose of this article is to evaluate whether voluntary traceability labelling, introduced by Regulation 1760/2000, can be considered a useful instrument for both the producers and consumers of meat products. Attention is focused on the vertical coordination effects of introducing voluntary labelling along the beef chain and on the interest the Italian consumer shows in labelled information on meat products. Two surveys were conducted: one addressing Italian meat organizations that signed voluntary labelling agreements and the other a sample of 1,025 Italian consumers. With regard to supply, the survey revealed that improved traceability led to a better redistribution of liability among the agents of the meat supply chain and to a strengthening of vertical agreements. Regarding the consumers, the results showed a notable consumer interest in the labelled information such as the meat origin and the information related to the system of cattle breeding, cattle feeding, and the date of slaughtering. © 2008 Wiley Periodicals, Inc., [source] Price transmission in the Spanish bovine sector: the BSE effectAGRICULTURAL ECONOMICS, Issue 1 2010Islam Hassouneh Food scare; BSE crisis; Price transmission; Regime-switching Abstract A regime-switching vector error correction model is applied to monthly price data to assess the impact of Bovine Spongiform Encephalopathy (BSE) outbreaks on price relationships and patterns of transmission among farm and retail markets for bovines in Spain. To evaluate the degree to which price transmission is affected by BSE food scares, a BSE food scare index is developed and used to determine regime switching. Results suggest that BSE scares affect beef producers and retailers differently. Consumer prices are found to be weakly exogenous and not found to react to BSE scares, while producer prices are conversely adjusted. The magnitude of the adjustment is found to depend on the magnitude of the BSE scare. [source] Failure of immunocompetitive capillary electrophoresis assay to detect disease-specific prion protein in buffy coat from humans and chimpanzees with Creutzfeldt-Jakob diseaseELECTROPHORESIS, Issue 5 2003Larisa Cervenakova Abstract The emergence of a new environmentally caused variant of Creutzfeldt-Jakob disease (vCJD), the result of food-born infection by the causative agent of bovine spongiform encephalopathy (BSE), has stimulated research on a practical diagnostic screening test. The immunocompetitive capillary electrophoresis (ICCE) assay has been reported to detect disease-specific, proteinase-resistant prion protein (PrPres) in the blood of scrapie-infected sheep. We have applied this method to blood from CJD-infected chimpanzees and humans. The threshold of detection achieved with our ICCE was 0.6 nM of synthetic peptide corresponding to the prion protein (PrP) C -terminus, and 2 nM of recombinant human PrP at the optimized conditions. However, the test was unable to distinguish between extracts of leucocytes from healthy and CJD-infected chimpanzees, and from healthy human donors and patients affected with various forms of CJD. Thus, the ICCE assay as presently performed is not suitable for use as a screening test in human transmissible spongiform encephalopathies (TSEs). [source] CSF analysis in patients with sporadic CJD and other transmissible spongiform encephalopathiesEUROPEAN JOURNAL OF NEUROLOGY, Issue 2 2007A. Green Patients with suspected Creutzfeldt,Jakob disease (CJD) often have routine cerebrospinal fluid (CSF) analysis performed to exclude treatable inflammatory conditions; however, little information is available about the range of results obtained for CSF tests in patients with sporadic CJD and other transmissible spongiform encephalopathies (TSE). Data from 450 patients with sporadic CJD and 47 patients with other TSEs were collected as part of an EC-supported multinational study. Raised white cell counts of >5 cells/,l were found in three of 298 patients with sporadic CJD, with two cell counts of 7 cells/,l and one of 20 cells/,l. Total protein concentrations of >0.9 g/l were found in five of 438 patients with sporadic CJD, although none had a concentration of >1 g/l. CSF oligoclonal IgG was detected in eight of 182 sporadic CJD patients. Of the patients with other TSEs, six had elevated cell counts ranging from 6 to 14 cells/,l but none had total protein concentrations of >0.9 g/l and one patient had detectable oligoclonal IgG. None of the patients with sporadic CJD or other TSEs had abnormalities in all three tests. [source] Codon 129 polymorphism and the E200K mutation do not affect the cellular prion protein isoform composition in the cerebrospinal fluid from patients with Creutzfeldt,Jakob diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2010Matthias Schmitz Abstract The cellular prion protein (PrPc) is a multifunctional, highly conserved and ubiquitously expressed protein. It undergoes a number of modifications during its post-translational processing, resulting in different PrPc glycoforms and truncated PrPc fragments. Limited data are available in humans on the expression and cleavage of PrPc. In this study we investigated the PrPc isoform composition in the cerebrospinal fluid from patients with different human prion diseases. The first group of patients was affected by sporadic Creutzfeldt,Jakob disease exhibiting different PrP codon 129 genotypes. The second group contained patients with a genetic form of Creutzfeldt,Jakob disease (E200K). The third group consisted of patients with fatal familial insomnia and the last group comprised cases with the Gerstmann,Sträussler,Scheinker syndrome. We examined whether the PrP codon 129 polymorphism in sporadic Creutzfeldt,Jakob disease as well as the type of prion disease in human patients has an impact on the glycosylation and processing of PrPc. Immunoblotting analyses using different monoclonal PrPc antibodies directed against various epitopes of PrPc revealed, for all examined groups of patients, a consistent predominance of the glycosylated PrPc isoforms as compared with the unglycosylated form. In addition, the antibody SAF70 recognized a variety of PrPc fragments with sizes of 21, 18, 13 and 12 kDa. Our findings indicate that the polymorphisms at PrP codon 129, the E200K mutation at codon 200 or the examined types of human transmissible spongiform encephalopathies do not exert a measurable effect on the glycosylation and processing of PrPc in human prion diseases. [source] Hyperefficient PrPSc amplification of mouse-adapted BSE and scrapie strain by protein misfolding cyclic amplification techniqueFEBS JOURNAL, Issue 10 2009Aiko Fujihara Abnormal forms of prion protein (PrPSc) accumulate via structural conversion of normal PrP (PrPC) in the progression of transmissible spongiform encephalopathy. Under cell-free conditions, the process can be efficiently replicated using in vitro PrPSc amplification methods, including protein misfolding cyclic amplification. These methods enable ultrasensitive detection of PrPSc; however, there remain difficulties in utilizing them in practice. For example, to date, several rounds of protein misfolding cyclic amplification have been necessary to reach maximal sensitivity, which not only take several weeks, but also result in an increased risk of contamination. In this study, we sought to further promote the rate of PrPSc amplification in the protein misfolding cyclic amplification technique using mouse transmissible spongiform encephalopathy models infected with either mouse-adapted bovine spongiform encephalopathy or mouse-adapted scrapie, Chandler strain. Here, we demonstrate that appropriate regulation of sonication dramatically accelerates PrPSc amplification in both strains. In fact, we reached maximum sensitivity, allowing the ultrasensitive detection of < 1 LD50 of PrPSc in the diluted brain homogenates, after only one or two reaction rounds, and in addition, we detected PrPSc in the plasma of mouse-adapted bovine spongiform encephalopathy-infected mice. We believe that these results will advance the establishment of a fast, ultrasensitive diagnostic test for transmissible spongiform encephalopathies. [source] Full-length prion protein aggregates to amyloid fibrils and spherical particles by distinct pathwaysFEBS JOURNAL, Issue 9 2008Driss El Moustaine As limited structural information is available on prion protein (PrP) misfolding and aggregation, a causative link between the specific (supra)molecular structure of PrP and transmissible spongiform encephalopathies remains to be elucidated. In this study, high pressure was utilized, as an approach to perturb protein structure, to characterize different morphological and structural PrP aggregates. It was shown that full-length recombinant PrP undergoes ,-sheet aggregation on high-pressure-induced destabilization. By tuning the physicochemical conditions, the assembly process evolves through two distinct pathways leading to the irreversible formation of spherical particles or amyloid fibrils, respectively. When the PrP aggregation propensity is enhanced, high pressure induces the formation of a partially unfolded aggregated protein, AggHP, which relaxes at ambient pressure to form amorphous aggregates. The latter largely retain the native secondary structure. On prolonged incubation at high pressure, followed by depressurization, AggHP transforms to a monodisperse population of spherical particles of about 20 nm in diameter, characterized by an essentially ,-sheet secondary structure. When the PrP aggregation propensity is decreased, an oligomeric reaction intermediate, IHP, is formed under high pressure. After pressure release, IHP relaxes to the original native structure. However, on prolonged incubation at high pressure and subsequent depressurization, it transforms to amyloid fibrils. Structural evaluation, using optical spectroscopic methods, demonstrates that the conformation adopted by the subfibrillar oligomeric intermediate, IHP, constitutes a necessary prerequisite for the formation of amyloids. The use of high-pressure perturbation thus provides an insight into the molecular mechanism of the first stages of PrP misfolding into amyloids. [source] Copper is required for prion protein-associated superoxide dismutase-l activity in Pichia pastorisFEBS JOURNAL, Issue 5 2007Carina Treiber The prion protein (PrP) is the key protein implicated in transmissible spongiform encephalopathies. It is a metalloprotein that binds manganese and copper. The latter is involved in the physiological function of the protein. We have previously found that PrP expression in Pichia pastoris affects intracellular metal ion concentrations and that formation of protease-resistant PrP is induced by additional copper and/or manganese. In this study, we show that heterologously expressed PrP is post-translationally modified and transported to the cell wall. We found by combining three different test systems that PrP itself had gained superoxide dismutase-like activity in P. pastoris. However, this activity could not be inhibited by KCN and depended on additional copper in the medium. Thus, this study defines the conditions under which PrP exhibits superoxide dismutase-like activity by showing that copper must be present for the protein to participate in scavenging and detoxification of reactive oxygen species. [source] Synthesis and structural characterization of a mimetic membrane-anchored prion proteinFEBS JOURNAL, Issue 6 2006Matthew R. Hicks During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP,GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP,GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP. [source] Pathogen safety of manufacturing processes for biological products: special emphasis on KOGENATE® BayerHAEMOPHILIA, Issue 2002D. C. Lee Summary., Manufacturers of human therapeutic proteins derived from biological sources continuously strive to improve the pathogen safety profiles of these products. Efforts to improve pathogen safety margins for these biological products are directed towards several areas within the manufacturing processes including: (a) sourcing and screening of raw materials (b) determining the potential for manufacturing processes to reduce pathogen titres, and (c) incorporating methods designed specifically to remove or inactivate contaminating pathogens. Methods that could potentially reduce pathogen titres are a major focus for many manufacturers. In general, these methods are grouped into two categories, pathogen clearance and pathogen inactivation. Assessments are performed on small-scale, laboratory simulations of the manufacturing process of interest that are spiked with a known amount of a selected pathogen. These studies provide estimates of the potential for a process step to remove or inactivate a particular pathogen. There are several pathogen clearance/inactivation methods that are inherent in manufacturing processes, however, some methods are intentionally incorporated into manufacturing for the sole purpose of reducing putative pathogen titres. Not only are well-known pathogens such as viruses targeted, but also suspected pathogens such as those associated with the transmissible spongiform encephalopathies (TSEs). The production processes for the isolation of several biological products, including recombinant KOGENATE® Bayer (Kogenate®FS), have been evaluated for the ability to reduce pathogen titres and/or have been designed to incorporate methods for reducing potential pathogen safety risks. Several processing steps with the potential to reduce pathogen titres have been identified. [source] New molecular markers of early and progressive CJD brain infectionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2004Zhi Yun Lu Abstract Transmissible spongiform encephalopathies (TSEs), including human Creutzfeldt,Jakob disease (CJD), are caused by a related group of infectious agents that can be transmitted to many mammalian species. Because the infectious component of TSE agents has not been identified, we examined myeloid cell linked inflammatory pathways to find if they were activated early in CJD infection. We here identify a specific set of transcripts in CJD infected mouse brains that define early and later stages of progressive disease. Serum amyloid A3 and L-selectin mRNAs were elevated as early as 20 days after intracerebral inoculation. Transcripts of myeloid cell recruitment factors such as MIP-1,, MIP-1,, and MCP1, as well as IL1, and TNF, were upregulated >10 fold between 30 and 40 days, well before prion protein (PrP) abnormalities that begin only after 80 days. At later stages of symptomatic neurodegenerative disease (100,110 days), a selected set of transcripts rose by as much as 100 fold. In contrast, normal brain inoculated controls showed no similar sequential changes. In sum, rapid and simple PCR tests defined progressive stages of CJD brain infection. These markers may also facilitate early diagnosis of CJD in accessible peripheral tissues such as spleen and blood. Because some TSE strains can differentially target particular cell types such as microglia, several of these molecular changes may also distinguish specific agent strains. The many host responses to the CJD agent challenge the assumption that the immune system does not recognize TSE infections because these agents are composed only of the host's own PrP. © 2004 Wiley-Liss, Inc. [source] Variant Creutzfeldt-Jakob disease: An unfolding epidemic of misfolded proteinsJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 6 2002P Horby Abstract: Variant Creutzfeldt-Jakob disease (vCJD) is an emerging infectious disease believed to be the human manifestation of bovine spongiform encephalopathy (BSE). Variant CJD belongs to a family of human and animal diseases called transmissible spongiform encephalopathies (TSE). The pathogenesis of TSE is not fully understood, but a modified form of a normal cellular protein plays a central role. Current measures to control vCJD aim to prevent transmission of the infectious agent from animals to humans through food or pharmaceutical products and to prevent transmission from person to person via medical interventions. The anticipated development of preclinical diagnostic tests and treatments for vCJD will create new control options and difficult choices. [source] Myiasis as a risk factor for prion diseases in humansJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 9 2006O Lupi Abstract Prion diseases are transmissible spongiform encephalopathies of humans and animals. The oral route is clearly associated with some prion diseases, according to the dissemination of bovine spongiform encephalopathy (BSE or mad cow disease) in cattle and kuru in humans. However, other prion diseases such as scrapie (in sheep) and chronic wasting disease (CWD) (in cervids) cannot be explained in this way and are probably more associated with a pattern of horizontal transmission in both domestic and wild animals. The skin and mucous membranes are a potential target for prion infections because keratinocytes and lymphocytes are susceptible to the abnormal infective isoform of the prion protein. Iatrogenic transmission of Creutzfeldt,Jakob disease (CJD) was also recognized after corneal transplants in humans and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes could also be important in prion infections. Some ectoparasites have been proven to harbour prion rods in laboratory experiments. Prion rods were identified in both fly larvae and pupae; adult flies are also able to express prion proteins. The most common causes of myiasis in cattle and sheep, closely related animals with previous prion infections, are Hypoderma bovis and Oestrus ovis, respectively. Both species of flies present a life cycle very different from human myiasis, as they have a long contact with neurological structures, such as spinal canal and epidural fat, which are potentially rich in prion rods. Ophthalmomyiases in humans is commonly caused by both species of fly larvae worldwide, providing almost direct contact with the central nervous system (CNS). The high expression of the prion protein on the skin and mucosa and the severity of the inflammatory response to the larvae could readily increase the efficiency of transmission of prions in both animals and humans. [source] 14-3-3 protein in the CSF of inflammatory peripheral neuropathiesJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2004A Bersano 14-3-3 proteins are a highly conserved protein family of unknown function, although some authors suggested a role in cellular proliferation and differentiation, neurotransmitters biosynthesis and apoptosis. The expression of these proteins increases during development, in particular, in large projection neurons such as spinal motor neurons. Recently the protein was described in cerebrospinal fluid (CSF) of patients with spongiform encephalopathies, in particular Creutzfeld-Jacob disease, where the protein is considered a highly sensitive and specific marker. 14-3-3 protein has been also detected in CSF of other prion-unrelated dementias and other neurodegenerative (Parkinson disease, stroke and paraneoplastic syndromes) and inflammatory diseases like Multiple Sclerosis. The aim of our study was to evaluate whether the 14-3-3 protein is also present in the CSF of peripheral nervous system diseases. We studied by Western Blot the CSF of 120 patients including 38 with Guillain-Barré syndrome (GBS), 23 with chronic inflammatory demyelinating polyneuropathy (CIDP), 12 with multifocal motor neuropathies (MMN), 20 motor neuron disease (MND), 8 paraneoplastic syndrome, 14 other neuropathies or radiculopathies (OPN), and 5 normal subjects (NC). We found the 14-3-3 protein in the CSF of 21 (55%) patients with GBS, 13 (56%) with CIDP, 1 (5%) with MND, 3 (21%) with OPN and none with paraneoplastic syndrome, MMN or NC. Our results reveal that 14-3-3 protein can be detected not only in central but also in peripheral nervous system diseases where it is significantly associated (p < 0.0001) with GBS and CIDP. [source] Spongiform encephalopathy mimicking corticobasal degenerationMOVEMENT DISORDERS, Issue 3 2002David J. Anschel MD The presentation of subacute spongiform encephalopathies (SSE) is varied. The following case of SSE presented clinically similar to corticobasal degeneration. The SSE diagnosis was suspected because of magnetic resonance imaging (MRI) findings and confirmed pathologically. © 2002 Movement Disorder Society [source] Neuroinvasion in sheep transmissible spongiform encephalopathies: the role of the haematogenous routeNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2009S. Sisó Background: It is generally believed that after oral exposure to transmissible spongiform encephalopathy (TSE) agents, neuroinvasion occurs via the enteric nervous system (ENS) and the autonomic nervous system. As a result, the dorsal motor nucleus of the vagus nerve is the initial point of disease-associated prion protein (PrPd) accumulation in the brain. Hypothesis and aim: If direct ENS invasion following oral infection results in an early and specific brain targeting for PrPd accumulation, such topographical distribution could be different when other routes of infection were used, highlighting distinct routes for neuroinvasion. Methods: An immunohistochemical study has been conducted on the brain of 67 preclinically infected sheep exposed to natural scrapie or to experimental TSE infection by various routes. Results: Initial PrPd accumulation consistently occurred in the dorsal motor nucleus of the vagus nerve followed by the hypothalamus, regardless of the breed of sheep, PrP genotype, TSE source and, notably, route of infection; these factors did not appear to affect the topographical progression of PrPd deposition in the brain either. Moreover, the early and consistent appearance of PrPd aggregates in the circumventricular organs, where the blood,brain barrier is absent, suggests that these organs can provide a portal for entry of prions when infectivity is present in blood. Conclusions: The haematogenous route, therefore, can represent a parallel or alternative pathway of neuroinvasion to ascending infection via the ENS/autonomic nervous system. [source] Pathogenetical significance of porencephalic lesions associated with intracerebral inoculation of sheep with the bovine spongiform encephalopathy (BSE) agentNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2009S. Sisó Decreased rates of transmission of transmissible spongiform encephalopathies (TSEs) to sheep have been attributed to some polymorphisms of the prion protein (PrP) and to a ,species barrier' on interspecies experiments. In addition, the blood,brain barrier may be a further impediment to TSE neuroinvasion. The intracerebral (I/C) route is generally considered the most efficient for TSE transmission, as it may help to bypass those factors. Therefore, susceptibility of particular species to specific TSE agents is conducted by this route. Aims: This study characterizes the traumatic brain lesions associated with the I/C injection of the bovine spongiform encephalopathy agent in sheep, assesses the relevance of such lesions in the outcome of clinical disease and provides insight into the mechanisms of PrPd conversion and amplification following I/C challenge. Methods: A total of 27 hemibrains have been macroscopically and immunohistochemically examined to investigate the presence of lesions compatible with the needle track and the PrPd distribution, respectively. Results: No residual inoculum was found and the extension and severity of the traumatic brain lesions were unrelated to the clinical outcome. Sheep with PrPd accumulation in the brain also showed conspicuous focal aggregates in the porencephalic lesions and in the circumventricular organs. In contrast, sheep without PrPd deposits in the brain were also negative in the traumatic lesions. Conclusion: Overall, these findings suggest that the efficiency of the I/C route is due to effective absorption and blood recirculation of infection, rather than to primary amplification at the site of injection. [source] Classical sheep transmissible spongiform encephalopathies: pathogenesis, pathological phenotypes and clinical diseaseNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2007M. Jeffrey 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 profiling). Differences in the inferred truncation sites of PrPd are found for different strains of sheep TSEs and for different infected cell types within individual strains. Immunochemical methods of characterizing strains broadly correspond to PrPd mapping discriminatory results, but distinct PrPd profiles, which provide strain- and source-specific information on both the cell types which sustain infection (cellular tropisms) and the cellular processing of PrPd, have no immunoblotting counterparts. The cause of neurological dysfunction in human is commonly considered to be neuronal loss secondary to a direct or indirect effect of the accumulation of PrPd. However, in sheep scrapie there is no significant neuronal loss, and relationships between different magnitudes, topographical and cytological forms of PrPd accumulation and clinical signs are not evident. PrPd accumulation also occurs in lymphoid tissues, for which there is indirect evidence of a pathological effect, in the peripheral nervous system and in other tissues. It is generally assumed that neuroinvasion results from infection of the enteric nervous system neurones subsequent to amplification of infectivity in lymphoid tissues and later spread via sympathetic and parasympathetic pathways. The evidence for this is, however, circumstantial. Accumulation of PrPd and presence of infectivity in tissues other than the nervous and lymphoreticular systems gives insights on the ways of transmission of infection and on food safety. [source] Disease-specific particles without prion protein in prion diseases , phenomenon or epiphenomenon?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2007P. P. Liberski 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. These particles have been viewed with caution by the scientific community because of the unverified or uninterpretable record of virus-like structures reported over the years in TSEs. TVS are spherical or tubular particles of approximate diameter 25,37 nm. They are smaller than synaptic vesicles, but larger than many particulate structures of the central nervous system, such as glycogen granules. Their electron density is higher compared with synaptic vesicles, and in experimental murine scrapie, they form paracrystalline arrays. None of these observations distinguish between TVS as an entity critical to the infectious process, or as a highly specific ultrastructural epiphenomenon, but their consistent presence in all TSEs demands further research. [source] Protein misfolding in neurodegenerative diseasesNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2004E. I. Agorogiannis A common pathogenic mechanism shared by diverse neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible spongiform encephalopathies, may be altered protein homeostasis leading to protein misfolding and aggregation of a wide variety of different proteins in the form of insoluble fibrils. Mutations in the genes encoding protein constituents of these aggregates have been linked to the corresponding diseases, thus a reasonable scenario of pathogenesis was based on misfolding of a neurone-specific protein that forms insoluble fibrils that subsequently kill neuronal cells. However, during the past 5 years accumulating evidence has revealed the neurotoxic role of prefibrillar intermediate forms (soluble oligomers and protofibrils) produced during fibril formation. Many think these may be the predominant neurotoxic species, whereas microscopically visible fibrillar aggregates may not be toxic. Large protein aggregates may rather be simply inactive, or even represent a protective state that sequesters and inactivates toxic oligomers and protofibrils. Further understanding of the biochemical mechanisms involved in protein misfolding and fibrillization may optimize the planning of common therapeutic approaches for neurodegenerative diseases, directed towards reversal of protein misfolding, blockade of protein oligomerization and interference with the action of toxic proteins. [source] Octapeptide repeat insertions increase the rate of protease-resistant prion protein formationPROTEIN SCIENCE, Issue 3 2006Roger A. Moore PrP, prion protein; HaPrP, hamster prion protein; TSE, transmissible spongiform encephalopathies Abstract A central feature of transmissible spongiform encephalopathies (TSE or prion diseases) involves the conversion of a normal, protease-sensitive glycoprotein termed prion protein (PrP-sen) into a pro-tease-resistant form, termed PrP-res. The N terminus of PrP-sen has five copies of a repeating eight amino acid sequence (octapeptide repeat). The presence of one to nine extra copies of this motif is associated with a heritable form of Creutzfeld-Jakob disease (CJD) in humans. An increasing number of octapeptide repeats correlates with earlier CJD onset, suggesting that the rate at which PrP-sen misfolds into PrP-res may be influenced by these mutations. In order to determine if octapeptide repeat insertions influence the rate at which PrP-res is formed, we used a hamster PrP amyloid-forming peptide (residues 23,144) into which two to 10 extra octapeptide repeats were inserted. The spontaneous formation of protease-resistant PrP amyloid from these peptides was more rapid in response to an increased number of octapeptide repeats. Furthermore, experiments using full-length glycosylated hamster PrP-sen demonstrated that PrP-res formation also occurred more rapidly from PrP-sen molecules expressing 10 extra copies of the octapeptide repeat. The rate increase for PrP-res formation did not appear to be due to any influence of the octapeptide repeat region on PrP structure, but rather to more rapid binding between PrP molecules. Our data from both models support the hypothesis that extra octapeptide repeats in PrP increase the rate at which protease resistant PrP is formed which in turn may affect the rate of disease onset in familial forms of CJD. [source] Competing intrachain interactions regulate the formation of ,-sheet fibrils in bovine PrP peptidesPROTEIN SCIENCE, Issue 3 2003Abdessamad Tahiri-Alaoui Abstract At the heart of the pathogenesis of transmissible spongiform encephalopathies (TSEs), such as BSE, scrapie, and Creutzfeldt,Jakob disease, lies a poorly understood structural rearrangement of PrP, an abundant glycoprotein of the nervous and lymphoid systems. The normal form (PrPC), rich in ,-helix, converts into an aberrant ,-sheet-dominated form (PrPSc), which seems to be at the center of the pathotoxic symptoms observed in TSEs. To understand this process better at a molecular level, we have studied the interactions between different peptides derived from bovine PrP and their structural significance. We show that two unstructured peptides derived from the central region of bovine PrP, residues 115,133 and 140,152, respectively, interact stoichiometrically under physiological conditions to generate ,-sheet-dominated fibrils. However, when both peptides are incubated in the presence of a third peptide derived from an adjoining ,-helical region (residues 153,169), the formation of ,-sheet-rich fibrils is abolished. These data indicate that native PrPC helix 1 might inhibit the strong intrinsic ,-sheet-forming propensity of sequences immediately N-terminal to the globular core of PrPC, by keeping in place intrachain interactions that would prevent these amyloidogenic regions from triggering aggregation. Moreover, these results indicate new ways in which PrPSc formation could be prevented. [source] Proteomic profiling of PrP27-30-enriched preparations extracted from the brain of hamsters with experimental scrapiePROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 15 2009Alessandra Giorgi Abstract Transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders characterized by the accumulation in the CNS of a pathological conformer (PrPTSE) of the host-encoded cellular prion protein (PrPC). PrPTSE has a central role in the pathogenesis of the disease but other factors are likely involved in the pathological process. In this work we employed a multi-step proteomic approach for the identification of proteins that co-purify with the protease-resistant core of PrPTSE (PrP27-30) extracted from brains of hamsters with experimental scrapie. We identified ferritin, calcium/calmodulin-dependent protein kinase , type II, apolipoprotein E, and tubulin as the major components associated with PrP27-30 but also trace amounts of actin, cofilin, Hsp90,, the , subunit of the T-complex protein 1, glyceraldehyde 3-phosphate dehydrogenase, histones, and keratins. Whereas some of these proteins (tubulin and ferritin) are known to bind PrP, other proteins (calcium/calmodulin-dependent protein kinase , type II, Hsp90,) may associate with PrPTSE fibrils during disease. Apolipoprotein E and actin have been previously observed in association with PrPTSE, whereas cofilin and actin were shown to form abnormal rods in the brain of patients with Alzheimer disease. The roles of these proteins in the development of brain lesions are still unclear and further work is needed to explain their involvement in the pathogenesis of TSEs. [source] Neurodevelopmental expression and localization of the cellular prion protein in the central nervous system of the mouseTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 11 2010Stefano Benvegnů Abstract Transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders caused by PrPSc, or prion, an abnormally folded form of the cellular prion protein (PrPC). The abundant expression of PrPC in the central nervous system (CNS) is a requirement for prion replication, yet despite years of intensive research the physiological function of PrPC still remains unclear. Several routes of investigation point out a potential role for PrPC in axon growth and neuronal development. Thus, we undertook a detailed analysis of the spatial and temporal expression of PrPC during mouse CNS development. Our findings show regional differences of the expression of PrP, with some specific white matter structures showing the earliest and highest expression of PrPC. Indeed, all these regions are part of the thalamolimbic neurocircuitry, suggesting a potential role of PrPC in the development and functioning of this specific brain system. J. Comp. Neurol. 518:1879,1891, 2010. © 2010 Wiley-Liss, Inc. [source] Neurodevelopmental expression and localization of the cellular prion protein in the central nervous system of the mouseTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 11 2010Stefano Benvegnů Abstract Transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders caused by PrPSc, or prion, an abnormally folded form of the cellular prion protein (PrPC). The abundant expression of PrPC in the central nervous system (CNS) is a requirement for prion replication, yet despite years of intensive research the physiological function of PrPC still remains unclear. Several routes of investigation point out a potential role for PrPC in axon growth and neuronal development. Thus, we undertook a detailed analysis of the spatial and temporal expression of PrPC during mouse CNS development. Our findings show regional differences of the expression of PrP, with some specific white matter structures showing the earliest and highest expression of PrPC. Indeed, all these regions are part of the thalamolimbic neurocircuitry, suggesting a potential role of PrPC in the development and functioning of this specific brain system. J. Comp. Neurol. 518:1879,1891, 2010. © 2010 Wiley-Liss, Inc. [source] Molecular analysis of carbohydrate N-acetylgalactosamine 4-O sulfotransferase 8 (CHST8) as a candidate gene for bovine spongiform encephalopathy susceptibilityANIMAL GENETICS, Issue 1 2010R. Morina Summary Endogenous prion proteins (PrP) play the central role in the pathogenesis of transmissible spongiform encephalopathies. The carbohydrate N -acetylgalactosamine 4-O sulfotransferase 8 (CHST8) promotes the conversion of the cellular PrPC into the pathogenic PrPd. Six sequence variants within the CHST8 gene were identified by comparative sequencing and genotyped for a sample of 623 animals comprising bovine spongiform encephalopathy (BSE)-affected and healthy control cows representing German Fleckvieh (German Simmental), German Holstein (Holstein-Friesian) and Brown Swiss. Significant differences in the allele, genotype and haplotype frequencies between BSE-affected and healthy cows indicate an association of sequence variant g.37254017G>T with the development of the disease in Brown Swiss cattle. [source] Gene and haplotype polymorphisms of the Prion gene (PRNP) in Japanese Brown, Japanese native and Holstein cattleANIMAL SCIENCE JOURNAL, Issue 5 2009George MSALYA ABSTRACT Polymorphisms in the prion protein gene (PRNP) are known to be associated with transmissible spongiform encephalopathies in human, sheep and goats. There is tentative association between PRNP promoter polymorphism and bovine spongiform encephalopathy (BSE) susceptibility in cattle. In this study, we genotyped for six bovine PRNP polymorphic sites including a 23-bp indel in the promoter, a 12-bp indel in the intron 1, two nonsynonymous single nucleotide polymorphisms (SNPs), octapeptide repeats in the coding region and a 14-bp indel in the 3,-untranslated region in 178 animals representing Japanese Brown, Kuchinoshima feral, Mishima, Japanese Shorthorn and Holstein. In 64 Japanese Brown cattle, three indel sites were polymorphic. All of the six sites were monomorphic in Kuchinoshima. The 23-bp and 12-bp indel sites were polymorphic in Mishima cattle. The 23-bp and 14-bp indel sites were polymorphic in Japanese Shorthorn cattle. Both SNP sites were monomorphic in all cattle examined in this study. At the 23-bp indel site, the genotype frequencies of Japanese Brown and Holstein breeds were similar to that of BSE affected cattle. We estimated 12 different haplotypes from these genotypic data. A ,23-12-K6S14+' haplotype was the major haplotype in all populations, whose frequencies ranged from 0.50 to 1.00. [source] In vivo prion protein intestinal uptake in fish,APMIS, Issue 3 2008ANDREA ZENONE DALLA VALLE Intestinal uptake of abnormal prion protein (PrPSc), the pathological agent involved in transmissible spongiform encephalopathies (TSEs), has been investigated in rainbow trout (Oncorhynchus mykiss). Experimental procedures were conducted in vivo by immunohistological PrPSc localization in intestine and pyloric caeca after forced feeding of infected material. Results indicate that PrPSc was absorbed by the intestinal mucosa and that it persisted in the fish gastrointestinal tract for up to 3 days in pyloric caeca and for up to 7 days in the distal intestine. It did not remain longer than 15 days in the fish intestine; furthermore, it did not cross the intestinal barrier. [source] Blood infectivity in transmissible spongiform encephalopathiesAPMIS, Issue 1 2002Ebbe Dickmeiss Blood infectivity in transmissible spongiform encephalopathies (TSE) is reviewed with special emphasis on transmission by blood transfusion in human beings. It is concluded that transmission by transfusion seems biologically plausible as regards variant Creutzfeld-Jakob Disease (vCJD), albeit present knowledge suggests that it is extremely uncommon. Precautionary measures against the putative risk of vCJD transmission by blood transfusion are discussed. [source] Aggregation characteristics of ovalbumin in ,-sheet conformation determined by spectroscopyBIOPOLYMERS, Issue 2 2002Raimon Sabaté Abstract Protein misfolding and aggregation are involved in a number of the so-called "conformational" diseases (e.g., transmissible spongiform encephalopathies and Alzheimer disease). The development of rational strategies to interfere with aggregation is a potential therapeutic approach that requires complete knowledge of the aggregation process. We studied the aggregation of ovalbumin in ,-sheet conformation using mainly the spectral changes in the spectra of two dyes (Congo Red and pinacyanol) caused by the aggregates. We assumed a linear model of polymerization that fit to the experimental data. The critical aggregation constant, concentration of half-aggregation, nucleation parameter, growth parameter, and number of aggregation and free energy changes (total and per residue) were determined as aggregation-related parameters. ,-Ovalbumin aggregates in a cooperative way. Moreover, the differences between such parameters obtained with Congo Red and pinacyanol suggest that each dye interacts with the protein in its own way. © 2002 John Wiley & Sons, Inc. Biopolymers (Biospectroscopy) 67: 113,120, 2002 [source] | |||||||||||||||||||||||||||||||