Coexistence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection
-----Original Message-----
From: Terry S. Singeltary Sr.
Sent: Monday, October 07, 2013 9:54 PM
To: CJD-L@LISTS.AEGEE.ORG
Subject: [CJD-L] Coexistence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection
Coexistence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection
Tracy Haldiman1, Chae Kim1, Yvonne Cohen1, Wei Chen1, Janis Blevins1, Liuting Qing1, Mark L. Cohen1, Jan Langeveld2, Glenn C. Telling3, Qingzhong Kong1 and Jiri G. Safar1* + Author Affiliations
1 Case Western Reserve University, United States;
2 Central Veterinary Institute of Wageningen UR, Netherlands;
3 Colorado State University, United States ↵* Corresponding author; email: jiri.safar@case.edu
Capsule
Background: Mechanism of prion adaptation and evolution has not been fully elucidated.
Results: Distinct human prion particles coexist and undergo competitive selection during replication.
Conclusion: Process is governed by preferential replication of the least stable pathogenic conformers.
Significance: Spectrum of conformers in wild human prion isolates enable adaptation and evolution by selection of the progressively less stable faster replicating subset.
Abstract
The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). The protein misfolding cyclic amplification (PMCA) replicates each of the PrPSc particle types independently, and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sCJD PrPSc is not a single conformational entity, but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers.
Molecular evolution Neurobiology Neurodegeneration Prions Protein conformation sporadic Creutzfeldt-Jakob disease Received July 9, 2013. Accepted August 23, 2013. Copyright © 2013, The American Society for Biochemistry and Molecular Biology
http://www.jbc.org/content/early/2013/08/23/jbc.M113.500108.abstract?papetoc
snip....
Concluding remarks and new directions. Several explanations have been proposed for the etiology of sporadic prion diseases, including spontaneous somatic mutations in the PRNP gene or rare stochastic conformational changes in the structure of PrPC (65). Whether the coexistent Type 1 and Type 2 PrPSc in sCJD is the result of such primordial event or evolution in the passage through different cells expressing differently posttranslationally modified PrPC remains to be established. When using new PrPC substrate that may differ in primary sequence, posttranslational modifications, or both, coexistent prions may undergo progressive conformational shifts due to the natural selection of the least stable conformers with the highest replication rate. Thus, the evolutionary conformational selection mechanism of PrPSc presented in this study may explain the recently observed acquisition of drug resistance by mammalian prions (66), and calls for the reevaluation of different therapeutic strategies targeting PrPSc. The high-resolution structural tools and the study of the role of PrPSc ligands must address the apparent conformational plasticity of PrPSc, which is likely responsible for the natural selection process of prions, and results in prion evolution and phenotypic diversity.
http://www.jbc.org/content/early/2013/08/23/jbc.M113.500108.full.pdf+html
http://creutzfeldt-jakob-disease.blogspot.com/
greetings cjd world,
I find this very interesting, this coesistence of different TSE prion strains from different TSE sources. this new/old study out reminds me of way back ;
According to Professor James Ironside of the National CJD Surveillance Unit, Miss Rimmer's case was "unique" and tests showed signs of both vCJD and new variant CJD.
"Our understanding of the case is not complete. It is one of the most unusual and difficult cases I have ever come across," he explained.
"The characteristics of the disease suffered by Miss Rimmer do not fall neatly into any category.
"The investigations that we have performed so far would indicate that this case, unique as it is, has more similarities to sporadic CJD than to new variant."
snip...
Mr Hughes returned a verdict of death by natural causes and concluded that Miss Rimmer died of bronchial pneumonia caused by CJD. ...
http://news.bbc.co.uk/2/hi/uk_news/wales/1300505.stm
Coexistence of multiple PrPSc types in individuals with CJD
http://neurology.thelancet.com
Published online October 31, 2005
Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease
Magdalini Polymenidou, Katharina Stoeck, Markus Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi
Summary Background
The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively.
Methods We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc.
Findings We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern.
Interpretation The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.
snip...
The above results set the existing CJD 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
Published online October 31, 2005
what i been saying for years, that the diagnostic criteria differentiating between the nvCJD (i.e. 'the chosen ones') and the sCJD (i.e. 'the forgotten ones') has been terribly flawed from the beginning. ....
TSS
HUMAN TSE USA 2005 Animal Prion Diseases Relevant to Humans (unknown types?)
Thu Oct 27, 2005 12:05 71.248.128.109
About Human Prion Diseases / Animal Prion Diseases Relevant to Humans 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.)
http://www.cjdsurveillance.com/abouthpd-animal.html
SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM 1997 TO 2004.
SPORADIC CJD CASES TRIPLED, and that is with a human TSE surveillance system that is terrible flawed. in 1997 cases of the _reported_ cases of cjd were at 54, to 163 _reported_ cases in 2004.
see stats here;
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???
http://www.cjdsurveillance.com/resources-casereport.html
CWD TO HUMANS = sCJD ???
AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.
snip...
http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf
ATYPICAL TSEs in USA CATTLE AND SHEEP ?
http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf
source ;
http://www.prwatch.org/node/4243
Wednesday, October 09, 2013
WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281 in compensation REVISED
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/why-ukbsenvcjd-only-theory-is-so.html
what does this mean, is the environment so loaded with the TSE prion that we are finding multiple strains in humans now ?
or does it mean that folks with multiple strains of human TSE detected in them, they are just the more lucky ones of a spontaneous happenstance of multiple bad luck events, that appear out of thin air, from more than one type of misfolding proteins ?
confucius is confused again. ...
kind regards, terry
CJD VOICE
http://creativegumbo.net/cjdvoice/
From: Terry S. Singeltary Sr.
Sent: Monday, October 07, 2013 9:54 PM
To: CJD-L@LISTS.AEGEE.ORG
Subject: [CJD-L] Coexistence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection
Coexistence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection
Tracy Haldiman1, Chae Kim1, Yvonne Cohen1, Wei Chen1, Janis Blevins1, Liuting Qing1, Mark L. Cohen1, Jan Langeveld2, Glenn C. Telling3, Qingzhong Kong1 and Jiri G. Safar1* + Author Affiliations
1 Case Western Reserve University, United States;
2 Central Veterinary Institute of Wageningen UR, Netherlands;
3 Colorado State University, United States ↵* Corresponding author; email: jiri.safar@case.edu
Capsule
Background: Mechanism of prion adaptation and evolution has not been fully elucidated.
Results: Distinct human prion particles coexist and undergo competitive selection during replication.
Conclusion: Process is governed by preferential replication of the least stable pathogenic conformers.
Significance: Spectrum of conformers in wild human prion isolates enable adaptation and evolution by selection of the progressively less stable faster replicating subset.
Abstract
The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). The protein misfolding cyclic amplification (PMCA) replicates each of the PrPSc particle types independently, and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sCJD PrPSc is not a single conformational entity, but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers.
Molecular evolution Neurobiology Neurodegeneration Prions Protein conformation sporadic Creutzfeldt-Jakob disease Received July 9, 2013. Accepted August 23, 2013. Copyright © 2013, The American Society for Biochemistry and Molecular Biology
http://www.jbc.org/content/early/2013/08/23/jbc.M113.500108.abstract?papetoc
snip....
Concluding remarks and new directions. Several explanations have been proposed for the etiology of sporadic prion diseases, including spontaneous somatic mutations in the PRNP gene or rare stochastic conformational changes in the structure of PrPC (65). Whether the coexistent Type 1 and Type 2 PrPSc in sCJD is the result of such primordial event or evolution in the passage through different cells expressing differently posttranslationally modified PrPC remains to be established. When using new PrPC substrate that may differ in primary sequence, posttranslational modifications, or both, coexistent prions may undergo progressive conformational shifts due to the natural selection of the least stable conformers with the highest replication rate. Thus, the evolutionary conformational selection mechanism of PrPSc presented in this study may explain the recently observed acquisition of drug resistance by mammalian prions (66), and calls for the reevaluation of different therapeutic strategies targeting PrPSc. The high-resolution structural tools and the study of the role of PrPSc ligands must address the apparent conformational plasticity of PrPSc, which is likely responsible for the natural selection process of prions, and results in prion evolution and phenotypic diversity.
http://www.jbc.org/content/early/2013/08/23/jbc.M113.500108.full.pdf+html
http://creutzfeldt-jakob-disease.blogspot.com/
greetings cjd world,
I find this very interesting, this coesistence of different TSE prion strains from different TSE sources. this new/old study out reminds me of way back ;
According to Professor James Ironside of the National CJD Surveillance Unit, Miss Rimmer's case was "unique" and tests showed signs of both vCJD and new variant CJD.
"Our understanding of the case is not complete. It is one of the most unusual and difficult cases I have ever come across," he explained.
"The characteristics of the disease suffered by Miss Rimmer do not fall neatly into any category.
"The investigations that we have performed so far would indicate that this case, unique as it is, has more similarities to sporadic CJD than to new variant."
snip...
Mr Hughes returned a verdict of death by natural causes and concluded that Miss Rimmer died of bronchial pneumonia caused by CJD. ...
http://news.bbc.co.uk/2/hi/uk_news/wales/1300505.stm
Coexistence of multiple PrPSc types in individuals with CJD
http://neurology.thelancet.com
Published online October 31, 2005
Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease
Magdalini Polymenidou, Katharina Stoeck, Markus Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi
Summary Background
The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrPSc), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrPSc display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively.
Methods We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrPSc.
Findings We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrPSc-rich brain areas, with a typical PrPSc type 1 migration pattern.
Interpretation The regular coexistence of multiple PrPSc types in patients with CJD casts doubts on the validity of electrophoretic PrPSc mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.
snip...
The above results set the existing CJD 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
Published online October 31, 2005
what i been saying for years, that the diagnostic criteria differentiating between the nvCJD (i.e. 'the chosen ones') and the sCJD (i.e. 'the forgotten ones') has been terribly flawed from the beginning. ....
TSS
HUMAN TSE USA 2005 Animal Prion Diseases Relevant to Humans (unknown types?)
Thu Oct 27, 2005 12:05 71.248.128.109
About Human Prion Diseases / Animal Prion Diseases Relevant to Humans 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.)
http://www.cjdsurveillance.com/abouthpd-animal.html
SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM 1997 TO 2004.
SPORADIC CJD CASES TRIPLED, and that is with a human TSE surveillance system that is terrible flawed. in 1997 cases of the _reported_ cases of cjd were at 54, to 163 _reported_ cases in 2004.
see stats here;
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???
http://www.cjdsurveillance.com/resources-casereport.html
CWD TO HUMANS = sCJD ???
AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.
snip...
http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf
ATYPICAL TSEs in USA CATTLE AND SHEEP ?
http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf
source ;
http://www.prwatch.org/node/4243
Wednesday, October 09, 2013
WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281 in compensation REVISED
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/why-ukbsenvcjd-only-theory-is-so.html
what does this mean, is the environment so loaded with the TSE prion that we are finding multiple strains in humans now ?
or does it mean that folks with multiple strains of human TSE detected in them, they are just the more lucky ones of a spontaneous happenstance of multiple bad luck events, that appear out of thin air, from more than one type of misfolding proteins ?
confucius is confused again. ...
kind regards, terry
CJD VOICE
http://creativegumbo.net/cjdvoice/
posted by Terry S. Singeltary Sr. at
9:40 AM
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