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Variant Creutzfeldt-Jakob disease in the United Kingdom and elsewhere: situation at the end of 2005 AM Molesworth (anna.molesworth@hpa.org.uk), NJ Andrews Health Protection Agency Centre for Infections, London, United Kingdom By the end of December 2005, a total of 159 cases of variant Creutzfeldt-Jakob disease (vCJD) had been reported in the United Kingdom, of which 153 have so far resulted in death. Elsewhere numbers remain small, with 15 cases in France, 4 in Ireland, 2 in the United States, and 1 each in Canada, Italy, Japan, the Netherlands, Portugal, Saudi Arabia and Spain [1,2]. Figure. vCJD deaths by year, and fitted quadratic model for incidence trend. This article was adapted by the authors from reference 2 http://www.eurosurveillance.org/ew/2006/060126.asp#4 [Article in Dutch] Jansen C, Houben MP, Hoff JI, Sanchez-Juan P, Rozemuller AJ, van Duijn CM. Afd. Pathologie, Universitair Medisch Centrum Utrecht, Postbus 85.500, 3508 GA Utrecht. c.jansen@lab.azu.nl A Dutch woman died at the age of 26 years, after a disease duration of 18 months, due to the new variant of Creutzfeldt-Jakob's disease (vCJD). She had never travelled to the United Kingdom and there was no history of potential iatrogenic exposure. However, she had worked in the catering and food production industry for the previous 6 years and had frequently consumed raw meat. The disease course showed the classical clinical picture of vCJD, which was confirmed by post-mortem examination of the brain. Contrary to classical sporadic CJD, patients with the variant disease are usually younger and present predominantly with psychiatric symptoms. Sensory complaints like pain and dysaesthesiae usually follow soon. Only later are these symptoms followed by rapidly progressive neurological symptoms and signs. All patients genotyped so far are homozygous for methionine on codon 129 of the prion protein gene. Recognition of the disease is of particular importance because of possible transmission via blood and tissues. In patients with rapidly progressive psychiatric symptoms and unexplained neurological signs, particularly sensory complaints, one must consider the possibility of vCJD. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16425845&query_hl=2&itool=pubmed_docsum Patient in the Netherlands diagnosed with variant Creutzfeldt-Jakob Disease A patient at the Mesos Medisch Centrum in Utrecht was diagnosed today with variant Creutzfeldt-Jakob Disease (vCJD), the human form of mad cow disease (BSE). This is the first known case of vCJD in the Netherlands. The case was reported by Rotterdam’s Erasmus Medisch Centrum, the national surveillance centre that monitors the disease in the Netherlands. The European surveillance centre for (variant) CJD in Edinburgh confirmed the diagnosis based on brain x-rays and the course of the disease. The Dutch National Health Inspectorate has launched an investigation to determine whether the disease may have been transmitted to others. The Dutch government has also notified European authorities of the case. VCJD is a variant of Creutzfeldt-Jakob Disease. Characterized by a spongy degeneration of the brain, the disease is caused by special protein structures (prions). It can be transmitted by tissue transplants and contaminated hospital instruments, especially during neurosurgical procedures. Recently, speculation has arisen that vCJD may be transmitted by blood based on two cases in the United Kingdom, where this may have occurred. However, no conclusive scientific evidence has been found to date. The patient concerned was never a blood or tissue donor, and never received any blood transfusions or tissue transplants. In light of that, it is highly improbable that this patient infected others or contracted the disease from someone else. In recent years, the Netherlands has introduced various measures to minimize the risk of transmission by blood: As of 1 September 2001: removal of white blood cells from all blood products (General Leukocyte Depletion). Other cases of vCJD have emerged in the past in European countries, starting in England. Ireland, France, Italy, Japan, Canada and the United States have also witnessed the occurrence of the disease. The Ministry of Agriculture, Nature and Food Quality’s website, www.minlnv.nl, provides additional information on BSE. http://www.minvws.nl/en/press/pg/2005/patient-in-the-netherlands-diagnosed-with-variant-creutzfeldt-jakob-disease.asp First case of Creutzfeldt-Jakob Disease in the Netherlands The first probable case of variant Creutzfeldt-Jakob (vCJD) disease in a patient in the Netherlands was reported on April 22nd 2005 by the Dutch Ministry of Health, Welfare and Sport. The patient is currently being treated at a hospital in Utrecht. The case, in a 26 year old woman, was detected through national surveillance of CJD, coordinated by the Erasmus Medical Centre in Rotterdam, and the probable diagnosis is based on magnetic resonance imaging (MRI) and clinical signs. The diagnosis was reviewed by the United Kingdom's National Creutzfeldt-Jakob Disease Surveillance Unit, which runs The European and Allied Countries Collaborative Study Group of CJD. The Netherlands has informed the European authorities via the European Early Warning and Response System (EWRS). http://www.minvws.nl/en/nieuwsberichten/pg/2005/first-case-of-creutzfeldt-jakob-disease-in-the-netherlands.asp Netherlands Reports First vCJD Case The Netherlands has become the fifth European country affected by variant Creutzfeldt-Jakob disease (vCJD), the human counterpart of bovine spongiform encephalopathy (BSE).On 21 April, health authorities reported that a 26-year-old woman had been diagnosed with the fatal brain affliction.The Netherlands has registered at least 77 cases of BSE. Of 171 cases of vCJD so far, 155 have occurred in the United Kingdom, nine in France, two in Italy, and one in Ireland. Four additional patients from outside Europe had all lived in the U.K. for varying periods. –MARTIN ENSERINK http://www.sciencemag.org/ HUMAN TSE USA 2005 Bovine Spongiform Encephalopathy (BSE) is a prion disease of cattle. Since 1986, when BSE was recognized, over 180,000 cattle in the UK have developed the disease, and approximately one to three million are likely to have been infected with the BSE agent, most of which were slaughtered for human consumption before developing signs of the disease. The origin of the first case of BSE is unknown, but the epidemic was caused by the recycling of processed waste parts of cattle, some of which were infected with the BSE agent and given to other cattle in feed. Control measures have resulted in the consistent decline of the epidemic in the UK since 1992. Infected cattle and feed exported from the UK have resulted in smaller epidemics in other European countries, where control measures were applied later. Compelling evidence indicates that BSE can be transmitted to humans through the consumption of prion contaminated meat. BSE-infected individuals eventually develop vCJD with an incubation time believed to be on average 10 years. As of November 2004, three cases of BSE have been reported in North America. One had been imported to Canada from the UK, one was grown in Canada, and one discovered in the USA but of Canadian origin. There has been only one case of vCJD reported in the USA, but the patient most likely acquired the disease in the United Kingdom. If current control measures intended to protect public and animal health are well enforced, the cattle epidemic should be largely under control and any remaining risk to humans through beef consumption should be very small. (For more details see Smith et al. British Medical Bulletin, 66: 185. 2003.) Chronic Wasting Disease (CWD) is a prion disease of elk and deer, both free range and in captivity. CWD is endemic in areas of Colorado, Wyoming, and Nebraska, but new foci of this disease have been detected in Nebraska, South Dakota, New Mexico, Wisconsin, Mississippi Kansas, Oklahoma, Minnesota, Montana, and Canada. Since there are an estimated 22 million elk and deer in the USA and a large number of hunters who consume elk and deer meat, there is the possibility that CWD can be transmitted from elk and deer to humans. As of November 2004, the NPDPSC has examined 26 hunters with a suspected prion disease. However, all of them appeared to have either typical sporadic or familial forms of the disease. The NPDPSC coordinates with the Centers for Disease Control and state health departments to monitor cases from CWD-endemic areas. Furthermore, it is doing experimental research on CWD transmissibility using animal models. (For details see Sigurdson et al. British Medical Bulletin. 66: 199. 2003 and Belay et al. Emerging Infectious Diseases. 10(6): 977. 2004.) p.s. please note the 47 PENDING CASES to Sept. 2005 p.s. please note the 2005 Prion D. total 120(8) 8=includes 51 type pending, 1 TYPE UNKNOWN ??? p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN??? p.s. please note 2004 prion disease (6) 6=7 TYPE UNKNOWN??? snip... http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf SPORADIC CJD Creutzfeldt-Jakob disease Summary ratio of protease-resistant prion protein (PrPSc), and type 2 PrPSc display unglycosylated core fragments of acids 82 and 97, respectively. Methods We generated anti-PrP monoclonal antibodies to K cleavage sites. These antibodies, which were Findings We studied 114 brain samples from 70 patients Every patient classified as CJD type 2, and all variant cerebellum and other PrPSc-rich brain areas, with a Interpretation The regular coexistence of multiple electrophoretic PrPSc mobilities as surrogates for classifications. into debate and introduce interesting questions about human CJD types. For example, do human prion types exist in a dynamic equilibrium in the brains of affected individuals? Do they coexist in most or even all CJD cases? Is the biochemically identified PrPSc type simply the dominant type, and not the only PrPSc species? http://neurology.thelancet.com Creutzfeldt-Jakob Disease Helen M. Yull,* Diane L. Ritchie,* Jan P.M. Langeveld,? Fred G. van Zijderveld,? Moira E. Bruce,? James W. Ironside,* and Mark W. Head* From the National CJD Surveillance Unit,* School of and Clinical Medicine, University of Edinburgh, Edinburgh, United Kingdom; Central Institute for Animal Disease (CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt- Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain. (Am J Pathol 2006, 168:151-157; DOI: 10.2353/ajpath.2006.050766) snip... Discussion In the apparent absence of a foreign nucleic acid genome associated with the agents responsible for transmissible spongiform encephalopathies or prion diseases, efforts to provide a molecular definition of agent strain have focused on biochemical differences in the abnormal, disease-associated form of the prion protein, termed PrPSc. Differences in PrPSc conformation and glycosylation have been proposed to underlie disease phenotype and form the biochemical basis of agent strain. This proposal has found support in the observation that the major phenotypic subtypes of sCJD appear to correlate with the presence of either type 1 or type 2 PrPSc in combination with the presence of either methionine or valine at codon 129 of the prion protein gene.2 Similarly, the PrPSc type associated with vCJD correlates with the presence of type 2 PrPSc and is distinct from that found in sCJD because of a characteristically high occupancy of both N-linked glycosylation sites (type 2B).6,11 The means by which such conformational difference is detected is somewhat indirect; relying on the action of proteases, primarily proteinase K, to degrade the normal Figure 6. Type 1 PrPSc is a stable minority component brain. Western blot analysis of PrP in a sample of of vCJD during digestion with proteinase K is shown. are indicated in minutes (T0, 5, 10, 30, 60, 120, 180). probed with 3F4, which detects both type 1 and type 2 which detects type 1. The insert shows a shorter course study from a separate experiment also probed included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Figure 7. A minority type 1-like PrPSc is found in vCJD to mice and in BSE. Western blot analysis of PrPSc in a sample of tonsil from a case of vCJD (Tonsil), in a of a wild-type mouse (C57BL) infected with vCJD and in BSE brain (BSE) is shown. Tissue extracts were digested Duplicate blots were probed with either 3F4 or 6H4, type 1 and type 2 PrPSc, and with 12B2, which detects included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155 AJP January 2006, Vol. 168, No. 1 cellular form of PrP and produce a protease-resistant core fragment of PrPSc that differs in the extent of its N-terminal truncation according to the original conformation. A complication has recently arisen with the finding that both type 1 and type 2 can co-exist in the brains of patients with sCJD.2,5-8 More recently this same phenomenon has been demonstrated in patients with iatrogenically acquired and familial forms of human prion disease. 9,10 The existence of this phenomenon is now beyond doubt but its prevalence and its biological remain a matter of debate. Conventional Western blot analysis using antibodies that detect type 1 and type 2 PrPSc has severe quantitative limitations for the co-detection of type 1 and type 2 PrPSc in individual samples, suggesting that the prevalence of co-occurrence of the two types might be underestimated. We have sought to circumvent this problem by using an antibody that is type 1-specific and applied this to the sole remaining human prion disease where the phenomenon of mixed PrPSc types has not yet been shown, namely vCJD. These results show that even in vCJD where susceptible individuals have been infected supposedly by a single strain of agent, both PrPSc types co-exist: a reminiscent of that seen when similarly discriminant antibodies were used to analyze experimental BSE in sheep.14,17 In sporadic and familial CJD, individual brains can show a wide range of relative amounts of the two types in samples from different regions, but where brains have been thoroughly investigated a predominant type is usually evident.2,6,10 This differs from this on vCJD, where type 1 is present in all samples but always as a minor component that never reaches a level at which it is detectable without a type 1-specific antibody. It would appear that the relative between type 1 and type 2 is controlled within certain limits in the vCJD brain. A minority type-1-like band is also detected by 12B2 in vCJD tonsil, in BSE brain and in the brains of mice experimentally infected with vCJD, suggesting that this balance of types is agent, rather than host or tissue, specific. Interestingly the signature" of the type 2 PrPSc found in vCJD (type 2B) is also seen in the type 1 PrPSc components, suggesting that it could legitimately be termed type 1B. PrPSc isotype analysis has proven to be extremely useful in the differential diagnosis of CJD and is continue to have a major role in the investigation of human prion diseases. However, it is clear, on the basis of these findings, that molecular typing has quantitative and that any mechanistic explanation of prion replication and the molecular basis of agent strain must accommodate the co-existence of multiple prion protein conformers. Whether or not the different conformers we describe here correlate in a simple and direct way with agent strain remains to be determined. In principle two interpretations present themselves: either the two conformers can be produced by a single strain of agent or vCJD (and, therefore, presumably BSE) results from a mixture of strains, one of which generally Evidence for the isolation in mice of more than one strain from individual isolates of BSE has been presented previously.18,19 One practical consequence of our findings is that the correct interpretation of transmission studies will depend on a full examination of the balance of molecular types present in the inoculum used to transmit disease, in to a thorough analysis of the molecular types that arise in the recipients. Another consequence relates to the diagnostic certainty of relying on PrPSc molecular type alone when considering the possibility of BSE or secondary transmission in humans who have a genotype other than methionine at codon 129 of the PRNP gene. In this context it is interesting to note minority type 1B component resembles the type 5 PrPSc described previously to characterize vCJD transmission into certain humanized PRNP129VV transgenic mouse models.12,20 This apparently abrupt change in molecular phenotype might represent a selection process imposed by this particular transgenic mouse model. Irrespective of whether this proves to be the case, the results shown here point to further complexities in the relationship the physico-chemical properties of the prion protein, human disease phenotype, and prion agent strain. Acknowledgments snip... Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157 AJP January 2006, Vol. 168, No. 1 ...TSS (2005), 31 , 565-579 doi: 10.1111/j.1365-2990.2005.00697.x © 2005 Blackwell Publishing Ltd 565 Blackwell Science, LtdOxford, UKNANNeuropathology and 316565579 Review article Phenotypic variability in human prion diseases J. W. Ironside, D. L. Ritchie and M. W. Head National Creutzfeldt-Jakob Disease Surveillance Unit, J. W. Ironside, D. L. Ritchie and M. W. Head (2005) Neuropathology and Applied Neurobiology 31, 565-579 Phenotypic variability in human prion diseases Human prion diseases are rare neurodegenerative disorders that can occur as sporadic, familial or acquired disorders. Within each of these categories there is a wide range of phenotypic variation that is not encountered in other neurodegenerative disorders. The identification of the prion protein and its key role in the pathogenesis of this diverse group of diseases has allowed a fuller of factors that influence disease phenotype. In particular, the naturally occurring polymorphism at codon 129 in the prion protein gene has a major influence on the phenotype in sporadic, familial and acquired prion diseases, although the underlying mechanisms remain unclear. Recent technical advances have improved our ability to study the isoforms of the abnormal prion protein in the brain and in other tissues. This has lead to the of molecular strain typing, in which different isoforms of the prion protein are proposed to correspond to individual strains of the transmissible agent, each with specific biological properties. In sporadic disease there are at least six major combinations of codon 129 genotype and prion protein isotype, which appear to relate to distinctive clinical subgroups of this disease. However, these relationships are proving to be more complex than first considered, particularly in cases with more than a single prion protein isotype in the brain. Further work is required to clarify these relationships and to explain the mechanism of neuropathological targeting of specific brain regions, which accounts for the diversity of clinical features within human prion diseases. © 2005 Blackwell Publishing Ltd, Neuropathology and sporadic CJD-like prion strains in transgenic mice expressing human prion protein The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002 Emmanuel A.Asante, Jacqueline M.Linehan, Melanie Desbruslais, Susan Joiner, Ian Gowland, Andrew L.Wood, Julie Welch, Andrew F.Hill, Sarah E.Lloyd, Jonathan D.F.Wadsworth and John Collinge1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.uk Variant Creutzfeldt±Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSEderived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure. snip... These studies further strengthen the evidence that vCJD is caused by a BSE-like prion strain. Also, remarkably, the key neuropathological hallmark of vCJD, the presence of abundant ¯orid PrP plaques, can be recapitulated on BSE or vCJD transmission to these mice. However, the most surprising aspect of the studies was the ®nding that an alternate pattern of disease can be induced in 129MM Tg35 mice from primary transmission of BSE, with a molecular phenotype indistinguishable from that of a of sporadic CJD. This ®nding has important potential implications as it raises the possibility that some humans infected with BSE prions may develop a clinical disease indistinguishable from classical CJD associated with type 2 PrPSc. This is, in our experience, the commonest molecular sub-type of sporadic CJD. In this regard, it is of interest that the reported incidence of sporadic CJD has risen UK since the 1970s (Cousens et al., 1997). This has been attributed to improved case ascertainment, particularly as much of the rise is reported from elderly patients and similar rises in incidence were noted in other European countries without reported BSE (Will et al., 1998). However, it is now clear that BSE is present in many European countries, albeit at a much lower incidence than was seen in the UK. While improved ascertainment is likely to be a major factor in this rise, that some of additional cases may be related to BSE exposure cannot be ruled out. It is of interest in this regard that a 2-fold increase in the reported incidence of sporadic CJD in 2001 has recently been reported for Switzerland, a country that had the highest incidence of cattle BSE in continental Europe between 1990 and 2002 (Glatzel et al., 2002). No epidemiological case±control studies with strati®cation of CJD cases by molecular sub-type have yet been reported. It will be important to review the incidence of sporadic CJD associated with PrPSc type 2 and other molecular in both BSE-affected and unaffected countries in the light of these ®ndings. If human BSE prion infection can result in propagation of type 2 PrPSc, it would be expected that such cases would be indistinguishable on clinical, pathological and molecular criteria from classical CJD. It may also be expected that such prions would behave biologically like those isolated from humans with sporadic CJD with type 2 PrPSc. The transmission properties of prions associated with type 2 PrPSc from BSE-inoculated 129MM Tg35 mice are being investigated by serial passage. We consider these data inconsistent with contamination of some of the 129MM Tg35 mice with sporadic CJD prions. These transmission studies were performed according to rigorous biosafety protocols for preparation of inocula and both the inoculation and care of mice, which are all uniquely identi®ed by sub-cutaneous transponders. However, crucially, the same BSE inocula have been used on 129VV Tg152 and 129MM Tg45 mice, which are highly sensitive to sporadic CJD but in which such transmissions producing type 2 PrPSc were not observed. Furthermore, in an independent experiment, separate inbred lines of wild-type mice, which are highly resistant to sporadic CJD prions, also propagated two distinctive PrPSc types on challenge with either BSE or vCJD. No evidence of spontaneous prion disease or PrPSc has been seen in groups of uninoculated or mock-inoculated aged 129MM Tg35 mice. While distinctive prion isolates have been derived from BSE passage in mice previously (designated 301C and 301V), these, in contrast to the data presented here, are propagated in mice expressing different prion proteins (Bruce et al., 1994). It is unclear whether our ®ndings indicate the existence of more than one prion strain in individual cattle with BSE, with selection and preferential replication of distinct strains by different hosts, or that `mutation' of a unitary BSE strain occurs in some types of host. Western blot analysis of single BSE isolates has not shown evidence of the presence of a proportion of monoglycosylated dominant PrPSc type in addition to the diglycosylated dominant pattern (data not shown). Extensive strain typing of large numbers of individual BSE-infected cattle either by biological or molecular methods has not been reported. Presumably, the different genetic background of the different inbred mouse lines is crucial in determining which prion strain propagates on BSE inoculation. The transgenic mice described here have a mixed genetic background with contributions from FVB/N, C57BL/6 and 129Sv inbred lines; each mouse will therefore have a different genetic background. This may explain the differing response of individual 129MM Tg35 mice, and the difference between 129MM Tg35 and 129MM Tg45 mice, which are, like all transgenic lines, populations derived from single founders. Indeed, the consistent distinctive strain propagation in FVB and C57BL/6 versus SJL and RIIIS lines may allow mapping of genes relevant to strain selection and propagation, and these studies progress. That different prion strains can be consistently isolated in different inbred mouse lines challenged with BSE prions argues that other species exposed to BSE may develop prion diseases that are not recognizable as being caused by the BSE strain by either biological or molecular strain typing methods. As with 129MM Tg35 mice, the prions replicating in such transmissions may be from naturally occurring prion strains. It remains of considerable concern whether BSE has transmitted to, and is being maintained in, European sheep ¯ocks. Given the diversity of sheep breeds affected by scrapie, it has to be considered that some sheep might have become infected with BSE, but propagated a distinctive strain type indistinguishable from those of natural sheep scrapie. ... The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002 6358 ãEuropean Molecular Biology Organization http://embojournal.npgjournals.com/cgi/reprint/21/23/6358 J Neuropsychiatry Clin Neurosci 17:489-495, November 2005 This study characterizes the type and timing of CONCLUSIONS Historically, psychiatric manifestations have been http://neuro.psychiatryonline.org/cgi/content/abstract/17/4/489 Personal Communication -------- Original Message -------- Valine 129 Prevents Expression of Variant CJD Phenotype Jonathan D. F. Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner, Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,* Sebastian Brandner, John Collinge. Variant Creutzfeldt-Jakob disease (vCJD) is a unique clinicopathological and molecular phenotype of human associated with infection with bovine spongiform prions. Here, we found that generation of this required expression of human prion protein (PrP) with Expression of human PrP with valine 129 resulted in a remarkably, persistence of a barrier to transmission of subpassage. Polymorphic residue 129 of human PrP distinct prion strains after BSE prion infection. Thus, human infection with BSE-derived prions may result in novel phenotypes in addition to vCJD, depending on the source and the recipient. snip... 3 DECEMBER 2004 VOL 306 SCIENCE http://www.sciencemag.org derived from bovine spongiform encephalopathy transmissions to inbred mice Sarah E. Lloyd, Jacqueline M. Linehan, Melanie Desbruslais, Susan Joiner, Jennifer Buckell, Sebastian Brandner, Jonathan D. F. Wadsworth and John Collinge Correspondence John Collinge j.collinge@prion.ucl.ac.uk MRC Prion Unit and Department of Neurodegenerative University College, London WC1N 3BG, UK Received 9 December 2003 Accepted 27 April 2004 Distinct prion strains can be distinguished by and biochemical properties of disease-associated prion Reliable comparisons of mouse prion strain properties genetically identical mice, as host prion protein to modulate prion disease phenotypes. While multiple sheep scrapie and Creutzfeldt-Jakob disease, bovine thought to be caused by a single prion strain. Primary of inbred mice resulted in the propagation of two prion strains may have been isolated. To investigate subpassaged in a single line of inbred mice (SJL) and strains had been identified. MRC1 was characterized by a mono-glycosylated-dominant PrPSc type and a deposits, while MRC2 displayed a much longer incubation a di-glycosylated-dominant PrPSc type and a distinct and neuronal loss. These data indicate a crucial prion strain selection and propagation in mice. It is may also be possible in BSE prion infection in humans snip... Journal of General Virology (2004), 85, 2471-2478 DOI http://vir.sgmjournals.org/cgi/content/abstract/85/8/2471 Cristina Casalone *, Gianluigi Zanusso , Pierluigi *Centro di Referenza Nazionale per le Encefalopatie Edited by Stanley B. Prusiner, University of Transmissible spongiform encephalopathies (TSEs), or C.C. and G.Z. contributed equally to this work. ||To whom correspondence should be addressed. E-mail: salvatore.monaco@mail.univr.it . www.pnas.org/cgi/doi/10.1073/pnas.0305777101 snip... Phenotypic Similarities Between BASE and sCJD. The of CJD brains was initially demonstrated in primates classification of atypical cases as CJD was based on (28). To date, no systematic studies of strain typing been provided, and classification of different subtypes on clinical, neuropathological, and molecular features PRNP codon 129 and the PrPSc glycotype) (8, 9, 15, 19). The importance of molecular PrPSc characterization in the identity of TSE strains is underscored by several showing that the stability of given disease-specific maintained upon experimental propagation of sCJD, familial CJD, and vCJD isolates in transgenic PrP-humanized mice (8, 29). Similarly, biochemical properties of BSE- and PrPSc molecules remain stable after passage to mice expressing bovine PrP (30). Recently, however, it has been reported that PrP-humanized mice inoculated with BSE may also propagate a distinctive PrPSc type, with a dominant'' pattern and electrophoretic mobility of the unglycosylated fragment slower than that of vCJD and Strikingly, this PrPSc type shares its molecular a PrPSc molecule found in classical sCJD. This variance with the PrPSc type found in MV2 sCJD cases and in cattle BASE, showing a monoglycosylated-dominant faster electrophoretic mobility of the as compared with BSE. In addition to molecular properties of PrPSc, BASE and MV2 sCJD share a distinctive pattern of intracerebral PrP deposition, which occurs as amyloid-kuru plaques. Differences were, however, the regional distribution of PrPSc. While inMV2 sCJD largest amounts of PrPSc were detected in the cerebellum, brainstem, and striatum, in cattle BASE these areas involved and the highest levels of PrPSc were recovered thalamus and olfactory regions. In conclusion, decoding the biochemical PrPSc signature of individual human and animal TSE strains may allow the of potential risk factors for human disorders with unknown etiology, such as sCJD. However, although BASE and sCJD share several characteristics, caution is dictated a link between conditions affecting two different mammalian species, based on convergent biochemical properties of PrPSc types. Strains of TSE agents may be better characterized upon passage to transgenic mice. In the until this is accomplished, our present findings epidemiological surveillance of cattle TSE and sCJD molecular criteria. http://www.pnas.org/cgi/reprint/0305777101v1 Published online before print March 20, 2001, Neurobiology * Commissariat à l'Energie Atomique, Service de Edited by D. Carleton Gajdusek, Centre National de la snip... Characterization of the CJD and Scrapie Strains. The lesion profiles of sCJD and iCJD differed only snip... http://www.pnas.org/cgi/content/full/041490898v1 Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC. Kuru and Creutzfeldt-Jakob disease of humans and PMID: 6997404 NOTES Interspecies Transmission of Chronic Wasting Disease Squirrel Monkeys (Saimiri sciureus) Richard F. Marsh,1? Anthony E. Kincaid,2 Richard A. Department of Animal Health and Biomedical Sciences, Physical Therapy2 and Department of Medical Nebraska 68178; and Department of Veterinary Molecular State University, Bozeman, Montana 597183 Received 3 May 2005/Accepted 10 August 2005 Chronic wasting disease (CWD) is an emerging prion to humans following exposure to CWD-infected tissues is primates to CWD, two squirrel monkeys were inoculated CWD-inoculated squirrel monkeys developed a progressive 31 and 34 months postinfection. Brain tissue from the isoform of the prion protein, PrP-res, and displayed transmission of CWD to primates. snip... JOURNAL OF VIROLOGY, Nov. 2005, p. 13794-13796 Vol. 0022-538X/05/$08.00!0 Copyright © 2005, American Society for Microbiology. ============================================= The EMBO Journal, Vol. 19, No. 17 pp. 4425-4430, 2000 Evidence of a molecular barrier limiting G.J. Raymond1, A. Bossers2, L.D. Raymond1, K.I. O?Rourke3, 1NIAID/NIH Rocky Mountain Laboratories, Hamilton, MT Abstract Chronic wasting disease (CWD) is a transmissible snip... Clearly, it is premature to draw firm conclusions about snip... Expedited Publication A subtype of sporadic prion disease mimicking fatal BACKGROUND: snip...END...TSS
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