Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy, iatrogenic transmission, what if?
Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy
Jacob I. Ayers, View ORCID Profile Joanne Lee, Octovia Monteiro, View ORCID Profile Amanda L. Woerman, Ann A. Lazar, Carlo Condello, Nick A. Paras, and View ORCID Profile Stanley B. Prusiner
aInstitute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158;
bDepartment of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158;
cDivision of Biostatistics, University of California, San Francisco, CA 94158;
dDivision of Oral Epidemiology and Dental Public Health, University of California, San Francisco, CA 94143;
eDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA 94158
PNAS February 8, 2022 119 (6) e2113489119; https://doi.org/10.1073/pnas.2113489119
Edited by Ted Dawson, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD; received July 29, 2021; accepted December 3, 2021 by Editorial Board Member James H. Hurley
Significance
Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are caused by α-synuclein prions that differ from each other and from those causing Parkinson’s disease (PD). DLB prions differ in their infectivity from those causing MSA or PD. The wild-type, normal version of the α-synuclein protein has the acidic amino acid glutamate (E) at residue 46, while in cases of inherited PD, it is mutated to the basic amino acid lysine (K). Using genetically engineered α-synuclein, we identified unique conditions for propagating MSA and DLB prions. Being able to distinguish among strains of naturally occurring α-synuclein prions may make it possible to develop strain-specific therapeutics for MSA, DLB, and PD.
Abstract
The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson’s disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.
snip...
α-Synuclein (E46K) Distinguishes Prion Strains.
To characterize α-synuclein prion activity from MSA brain samples, we infected several HEK cell lines overexpressing α-synuclein fused to YFP (18). While one cell line expressed WT α-synuclein, three others expressed human α-synuclein containing point mutations causing fPD. These three mutations are A30P, E46K, and A53T (18). As discussed in the Introduction, cells expressing E46K α-synuclein protein abolished formation of nascent MSA α-synuclein prions, while cells expressing WT, A30P, or A53T α-synuclein protein displayed a robust induction of fluorescent puncta upon infection with the same MSA samples (18). In contrast, recombinant α-synuclein fibrils were capable of infecting all cell lines tested. Based upon these results, we concluded that MSA α-synuclein prions are likely to be conformationally distinct from PD prions (18). However, due to the inability of homogenates from PD patients to infect these cell lines, we were unable to more conclusively test this hypothesis.
Next, to ensure that PK/PTA precipitation did not alter the selectivity of MSA α-synuclein prions to these different HEK cell models and to characterize the putative activity of PD and DLB α-synuclein prions, we tested these samples in WT, A30P, and E46K cell lines. MSA PK/PTA samples (n = 5) retained their ability to infect HEK cells expressing α-syn140*WT-YFP, α-syn140*A30P-YFP, and α-syn140*A53T-YFP and displayed high levels of infectivity (Fig. 2 and Table 1). In comparison, infection of the same cell lines using PK/PTA samples from PD (n = 5) and DLB homogenates (n = 6) resulted in significant levels of infectivity from only one of the five PD samples (PD16), and in three of the six DLB samples (Fig. 2 and Table 1). Treatment with the PD/DLB samples resulted in lower levels of infectivity than treatment with MSA samples in all three cell lines. In addition, we also observed differences in the size of the aggregates induced in the three α-synuclein–expressing cell lines. The MSA samples were capable of inducing large punctate aggregates, whereas those induced by both the PD and DLB cases were noticeably smaller (Fig. 2 B, D, and F).
Discussion
Transmission of α-synuclein prions from human brains to experimental hosts ranging from cultured cells to nonhuman primates was unsuccessful for decades (9). The first indication of transmissibility was a report that Lewy body pathology had been transmitted from the putamen of PD patients to fetal striatal tissue transplanted in the striatum (28⇓–30). Since these fetal transplants proved ineffective as a treatment for advanced PD, few similar procedures have been subsequently performed. Notably, many experimental studies demonstrating α-synuclein prion infectivity have consisted of injecting recombinant α-synuclein fibrils, sometimes called preformed fibrils, into the brains of TgM83+/− mice (31⇓–33).
During our initial study of α-synuclein mutations, we found that MSA brain homogenates were infectious in both TgM83+/− mice and HEK cells overexpressing α-synuclein containing the A53T mutation (15, 16, 19, 31). In parallel studies of homogenates from PD brains, we found little evidence for α-synuclein prion infectivity (16). Although PTA precipitation alone was sufficient for measuring MSA prion activity, it was unable to facilitate α-synuclein prion infectivity from PD brain homogenates (15, 16, 19). In other studies, detergent-insoluble fractions prepared from MSA and PD homogenates were added to HEK cells overexpressing α-syn*A53T fused to YFP; three of the five PD extracts and four of the five MSA extracts showed evidence for α-synuclein prion replication (21). Notably, the detergent-soluble fractions from MSA but not PD retained significant prion activity. Additionally, Recasens and colleagues isolated aggregates of α-synuclein from human PD brains using sucrose gradients, and upon intracerebral inoculation of these extracts into WT mice and macaque monkeys, a modest level of degeneration of nigrostriatal neurons was detected (34). Taken together, these studies raise the possibility that special conditions are needed to liberate PD α-synuclein prions sequestered inside Lewy bodies. Consistent with this hypothesis, ultrastructural characterization of Lewy bodies shows a crowded environment consisting of not only α-synuclein but also of membranes and organelles all densely packed into inclusions (35).
Friday, January 29, 2016
Synucleinopathies: Past, Present and Future, iatrogenic, what if?
Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy, iatrogenic transmission, what if?
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
sporadic CJD, along with new TSE prion disease in humans, of which the young are dying, of which long duration of illness from onset of symptoms to death have been documented, only to have a new name added to the pot of prion disease i.e. sporadic GSS, sporadic FFI, and or VPSPR.
I only ponder how a familial type disease could be sporadic with no genetic link to any family member?
when the USA is the only documented Country in the world to have documented two different cases of atypical H-type BSE, with one case being called atypical H-G BSE with the G meaning Genetic, with new science now showing that indeed atypical H-type BSE is very possible transmitted to cattle via oral transmission (Prion2014). sporadic CJD and VPSPR have been rising in Canada, USA, and the UK, with the same old excuse, better surveillance.
You can only use that excuse for so many years, for so many decades, until one must conclude that CJD TSE prion cases are rising. a 48% increase in CJD in Canada is not just a blip or a reason of better surveillance, it is a mathematical rise in numbers.
More and more we are seeing more humans exposed in various circumstance in the Hospital, Medical, Surgical arenas to the TSE Prion disease, and at the same time in North America, more and more humans are becoming exposed to the TSE prion disease via consumption of the TSE prion via deer and elk, cattle, sheep and goats, and for those that are exposed via or consumption, go on to further expose many others via the iatrogenic modes of transmission of the TSE prion disease i.e. friendly fire.
I pondered this mode of transmission via the victims of sporadic FFI, sporadic GSS, could this be a iatrogenic event from someone sub-clinical with sFFI or sGSS ? what if?
Wednesday, May 16, 2012
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Terry S. Singeltary Sr. Proposal ID: 29403
Thursday, March 8, 2018
Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein
Furthermore, GSS A117V infected vole brains were able to induce the same disease phenotype in recipient voles within 3–4 months after challenge, proving that a prion agent propagated in the brains of infected animals. These findings imply that brains of GSS patients harbor infectious prions with transmissibility features similar to those found in other human and animal TSEs.
*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery ***
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Greetings Friends, Neighbors, and Colleagues,
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Confucius is confused again.
I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.
what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???
it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.
sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.
I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.
I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease???
in question, by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?
this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.
THURSDAY, FEBRUARY 15, 2018
Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study
http://creutzfeldt-jakob-disease.blogspot.com/2018/02/iatrogenic-creutzfeldt-jakob-disease.html
Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study
http://creutzfeldt-jakob-disease.blogspot.com/2018/02/iatrogenic-creutzfeldt-jakob-disease.html
Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
snip...see full Singeltary Nature comment here;
Alzheimer's disease
let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...
Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
IN CONFIDENCE
5 NOVEMBER 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication.
There are also results to be made available shortly
(1) concerning a farmer with CJD who had BSE animals,
(2) on the possible transmissibility of Alzheimer’s and
(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
snip...see full Singeltary Nature comment here;
re-Evidence for human transmission of amyloid-? pathology and cerebral amyloid angiopathy Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.
First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.
Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.
where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?
we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.
That 'anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.
The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients, who got pooled extracts injected from thousands of cadavers, were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.
That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find 'alarming' is pathetic.
Sounds like the journalists had it right in the first place: 'Alzheimer's may be a transmissible infection' in The Independent to 'You can catch Alzheimer's' in The Daily Mirror or 'Alzheimer's bombshell' in The Daily Express
if not for the journalist, the layperson would not know about these important findings.
where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?
when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.
to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer's, the price of poker goes up drastically.
so, who makes that final decision, and how many more decades do we have to wait?
the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?
Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.
FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.
in my opinion, it's one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.
greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it's bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer's of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.
I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...
2012
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Background
Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.
Methods
Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.
Results
I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.
Conclusions
There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.
end...tss
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
source references ...end...tss
Hello Nicole,
by all means, please do use my poster. but I thought this was already taken care of, and I could not attend for my poster presentation, therefore, it was not going to be presented. I have some health issues and could not make the trip.
please see old correspondence below...
From: Nicole Sanders Sent: Tuesday, April 10, 2012 5:37 PM To: Terry S. Singeltary Sr. Subject: RE: re-submission
Dear Terry,
The decline of proposal number 30756 is registered in the system. Thank you for your consideration.
Best Regards,
Nicole
Nicole Sanders
Senior Specialist, Membership & Conference Programming
______________________________________
From: xxxx
To: Terry Singeltary
Sent: Saturday, December 05, 2009 9:09 AM
Subject: 14th ICID - abstract accepted for 'International Scientific Exchange'
Your preliminary abstract number: 670
Dear Mr. Singeltary,
On behalf of the Scientific Committee, I am pleased to inform you that your abstract
'Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009'
WAS accepted for inclusion in the INTERNATIONAL SCIENTIFIC EXCHANGE (ISE) section of the 14th International Congress on Infectious Diseases. Accordingly, your abstract will be included in the "Intl. Scientific Exchange abstract CD-rom" of the Congress which will be distributed to all participants.
Abstracts accepted for INTERNATIONAL SCIENTIFIC EXCHANGE are NOT PRESENTED in the oral OR poster sessions.
Your abstract below was accepted for: INTERNATIONAL SCIENTIFIC EXCHANGE
#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
Author: T. Singeltary; Bacliff, TX/US
Topic: Emerging Infectious Diseases Preferred type of presentation: International Scientific Exchange
This abstract has been ACCEPTED.
#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
Authors: T. Singeltary; Bacliff, TX/US
Title: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
Body: Background
An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
Methods
12 years independent research of available data
Results
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries.
I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
Keywords: Transmissible Spongiform Encephalopathy Creutzfeldt Jakob Disease Prion
page 114 ;
http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf
http://www.isid.org/14th_icid/
http://www.isid.org/publications/ICID_Archive.shtml
http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf
Background
Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.
Methods
Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.
Results
I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.
Conclusions
There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.
end...tss
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
source references ...end...tss
Hello Nicole,
by all means, please do use my poster. but I thought this was already taken care of, and I could not attend for my poster presentation, therefore, it was not going to be presented. I have some health issues and could not make the trip.
please see old correspondence below...
From: Nicole Sanders Sent: Tuesday, April 10, 2012 5:37 PM To: Terry S. Singeltary Sr. Subject: RE: re-submission
Dear Terry,
The decline of proposal number 30756 is registered in the system. Thank you for your consideration.
Best Regards,
Nicole
Nicole Sanders
Senior Specialist, Membership & Conference Programming
______________________________________
From: xxxx
To: Terry Singeltary
Sent: Saturday, December 05, 2009 9:09 AM
Subject: 14th ICID - abstract accepted for 'International Scientific Exchange'
Your preliminary abstract number: 670
Dear Mr. Singeltary,
On behalf of the Scientific Committee, I am pleased to inform you that your abstract
'Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009'
WAS accepted for inclusion in the INTERNATIONAL SCIENTIFIC EXCHANGE (ISE) section of the 14th International Congress on Infectious Diseases. Accordingly, your abstract will be included in the "Intl. Scientific Exchange abstract CD-rom" of the Congress which will be distributed to all participants.
Abstracts accepted for INTERNATIONAL SCIENTIFIC EXCHANGE are NOT PRESENTED in the oral OR poster sessions.
Your abstract below was accepted for: INTERNATIONAL SCIENTIFIC EXCHANGE
#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
Author: T. Singeltary; Bacliff, TX/US
Topic: Emerging Infectious Diseases Preferred type of presentation: International Scientific Exchange
This abstract has been ACCEPTED.
#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
Authors: T. Singeltary; Bacliff, TX/US
Title: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
Body: Background
An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
Methods
12 years independent research of available data
Results
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries.
I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
Keywords: Transmissible Spongiform Encephalopathy Creutzfeldt Jakob Disease Prion
page 114 ;
http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf
http://www.isid.org/14th_icid/
http://www.isid.org/publications/ICID_Archive.shtml
http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf
Thursday, December 3, 2015
Transmission of Soluble and Insoluble α-Synuclein to Mice
Journal of Neuropathology & Experimental Neurology:
December 2015 - Volume 74 - Issue 12 - p 1158–1169
doi: 10.1097/NEN.0000000000000262
Original Articles
Transmission of Soluble and Insoluble α-Synuclein to Mice
Jones, Daryl Rhys PhD; Delenclos, Marion PhD; Baine, AnnMarie T.; DeTure, Michael PhD; Murray, Melissa E. PhD; Dickson, Dennis W. MD; McLean, Pamela J. PhD
Supplemental Author Material
Abstract:
The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.
© 2015 by American Association of Neuropathologists, Inc.
Research
Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein
Maria E. Bernis1, Affiliated with Julius T. Babila1, Affiliated with Sara Breid1, Affiliated with Katharina Annick Wüsten1, Affiliated with Ullrich Wüllner1, 2 and Affiliated with Gültekin Tamgüney1Email author Affiliated with Acta Neuropathologica Communications20153:75 DOI: 10.1186/s40478-015-0254-7
© Bernis et al. 2015
Received: 6 November 2015
Accepted: 6 November 2015
Published: 26 November 2015
Abstract
Introduction Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that are characterized by the intracellular accumulation of alpha-synuclein containing aggregates. Recent increasing evidence suggests that Parkinson’s disease and MSA pathology spread throughout the nervous system in a spatiotemporal fashion, possibly by prion-like propagation of alpha-synuclein positive aggregates between synaptically connected areas. Concurrently, intracerebral injection of pathological alpha-synuclein into transgenic mice overexpressing human wild-type alpha-synuclein, or human alpha-synuclein with the familial A53T mutation, or into wild-type mice causes spreading of alpha-synuclein pathology in the CNS. Considering that wild-type mice naturally also express a threonine at codon 53 of alpha-synuclein, it has remained unclear whether human wild-type alpha-synuclein alone, in the absence of endogenously expressed mouse alpha-synuclein, would support a similar propagation of alpha-synuclein pathology in vivo.
Results
Here we show that brain extracts from two patients with MSA and two patients with probable incidental Lewy body disease (iLBD) but not phosphate-buffered saline induce prion-like spreading of pathological alpha-synuclein after intrastriatal injection into mice expressing human wild-type alpha-synuclein. Mice were sacrificed at 3, 6, and 9 months post injection and analyzed neuropathologically and biochemically. Mice injected with brain extracts from patients with MSA or probable iLBD both accumulated intraneuronal inclusion bodies, which stained positive for phosphorylated alpha-synuclein and appeared predominantly within the injected brain hemisphere after 6 months. After 9 months these intraneuronal inclusion bodies had spread to the contralateral hemisphere and more rostral and caudal areas. Biochemical analysis showed that brains of mice injected with brain extracts from patients with MSA and probable iLBD contained hyperphosphorylated alpha-synuclein that also seeded aggregation of recombinant human wild-type alpha-synuclein in a Thioflavin T binding assay.
Conclusions Our results indicate that human wild-type alpha-synuclein supports the prion-like spreading of alpha-synuclein pathology in the absence of endogenously expressed mouse alpha-synuclein in vivo.
SNIP...
Conclusions
We show that human wild-type alpha-synuclein by itself, in the absence of endogenously expressed mouse alpha-synuclein, supports a prion-like mechanism in the spreading of pathological alpha-synuclein, which does not necessitate the presence of fulminant Lewy body-type pathology. In our experiments sarkosyl-soluble pathogenic alpha-synuclein species, which need to be further characterized, were readily transmitted between neurons supporting the concept that the appearance of additional detergent-insoluble alpha-synuclein species and Lewy body pathology may represent a late cellular event in mature synucleinopathies [19, 34, 41]. Consequentially, potential therapeutic strategies targeting the interneuronal spread of soluble pathogenic alpha-synuclein in synucleinopathies such as PD or MSA may be promising but effective only early in the disease process.
Ethical approval All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Keywords Parkinson’s disease Multiple system atrophy Incidental Lewy body disease alpha-synuclein Synucleinopathy Prion-like
Tuesday, December 1, 2015
Sorting Out Release, Uptake and Processing of Alpha-Synuclein During Prion-Like Spread of Pathology
O.01: Transgenic mice expressing human wild-type a-synuclein develop neuropathology after inoculation with brain homogenates from patients with multiple system atrophy or aged subjects without neurological disorder
Maria Eugenia Bernis1, Julius Tachu Babila1, Sara Breid1, Ullrich W€ullner1,2, and G€ultekin Tamg€uney1 1German Center for Neurodegenerative Diseases (DZNE); Bonn, Germany; 2Department of Neurology; University of Bonn; Bonn, Germany
Multiple system atrophy (MSA) and Parkinson’s disease are synucleinopathies that are defined by the presence of aggregated and hyperphosphorylated a-synuclein (a-syn) within cells of the central nervous system (CNS). Recent findings suggest that pathological a-syn may spread prion-like within the nervous system. We investigated prion-like propagation of pathological a-syn in Tg(SNCA)1Nbm/J mice that do not express mouse but low levels of human wt a-syn and do not naturally develop any pathology or neurodegenerative disease.
We inoculated brain homogenate from 2 patients with MSA, from 2 aged control subjects without neurological disorder, or saline intrastriatally into Tg(SNCA)1Nbm/J mice. Challenged mice were sacrificed at 90, 180, and 270 d post inoculation and were analyzed biochemically and immunohistochemically for pathological a-syn.
Brain homogenates from MSA or aged control subjects but not saline triggered progressive accumulation of aggregated a-syn in neurons of inoculated mice. Aggregates of a-syn were hyperphosphorylated and costained for p62 that targets proteins for degradation. Aggregates of pathological a-syn were first observable in the ipsilateral brain hemisphere and over time in the contralateral hemisphere and in more rostral and caudal areas.
Our findings show that brain homogenate from MSA patients but not saline induces pathological changes in the CNS of Tg(SNCA) 1Nbm/J mice. Our data support that pathological a-syn may propagate prion-like along neuronal networks. Furthermore, human wt a-syn supports propagation of pathological a-syn. Intriguingly, brain homogenate from aged control subjects without neurological disorder equally induced synucleinopathy in brains of Tg(SNCA)1Nbm/J mice suggesting that aged human brains can contain pathological a-syn.
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O.02: Experimental transmissibility of mutant SOD1 motor neuron disease
Jacob Ayers, Susan Fromholt, Morgan Koch, Adam DeBosier, Ben McMahon, Guilian Xu, and David Borchelt University of Florida; Gainesville, FL USA
By unknown mechanisms, the symptoms of amyotrophic lateral sclerosis (ALS) seem to spread along anatomical pathways to engulf the motor nervous system. The rate at which symptoms spread is one of the primary drivers of disease progression. One mechanism by which ALS symptoms could spread is by a prion-like propagation of a toxic misfolded protein from cell to cell along anatomic pathways. Proteins that can transmit toxic conformations between
S1 Prion, 9:S1–S10, 2015 ISSN: 1933-6896 print / 1933-690X online
cells often can also experimentally transmit disease between individual organisms. To survey the ease with which motor neuron disease (MND) can be transmitted, we injected spinal cord homogenates prepared from paralyzed mice expressing mutant superoxide dismutase 1 (SOD1-G93A and G37R) into the spinal cords of genetically vulnerable SOD1 transgenic mice. From the various models we tested, one emerged as showing high vulnerability. Tissue homogenates from paralyzed G93A expressing mice induced MND in 6 of 10 mice expressing low levels of G85R-SOD1 fused to yellow fluorescent protein (G85R-YFP mice) by 3– 11 months, and produced widespread spinal inclusion pathology. Importantly, second passage of homogenates from G93A!G85R-YFP mice back into newborn G85R-YFP mice, induced disease in 4 of 4 mice by 3 months of age. Homogenates from paralyzed mice expressing the G37R variant were among those that transmitted poorly regardless of the strain of recipient transgenic animal injected, a finding suggestive of strain-like properties that manifest as differing abilities to transmit MND. Together, our data provide a working model for MND transmission to study the pathogenesis of ALS.
Tuesday, September 1, 2015
Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism
Wednesday, September 2, 2015
Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer’s Disease Database
Tuesday, June 30, 2015
PRION2015 Alzheimer’s disease
Tuesday, November 26, 2013
Transmission of multiple system atrophy prions to transgenic mice
Sunday, February 10, 2013
Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?
Wednesday, September 21, 2011
PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)
Wednesday, January 5, 2011
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions
David W. Colby1,* and Stanley B. Prusiner1,2
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
Second death in France in a laboratory working on prions
Creutzfeldt-Jakob disease has killed a person who handled this infectious agent at Inrae in Toulouse. After a first death in 2019, a moratorium on work on this pathogen has been extended.
By Hervé Morin
Creutzfeldt-Jakob disease killed a few days ago a retired research technician from the National Research Institute for Agriculture, Food and the Environment (Inrae), who had worked in Toulouse in contact of biological tissue infected with prions. This death sows consternation and concern in the scientific community working with these infectious agents. It follows the death, on June 17, 2019, of Emilie Jaumain, a 33-year-old laboratory technician, suffering from the same incurable neurodegenerative disease. The young woman is said to have contracted it in 2010, cutting herself while handling fragments of the brains of mice infected with prions, in another unit of INRAE, in Jouy-en-Josas.
Computer representation of part of a prion protein on a light micrograph of pyramidal nerve cells (neurons, in black) in the cerebellum of the brain. ALFRED PASIEKA / SCIENCE PHOTO LIBRARY
Regarding the retiree from Toulouse, it will be necessary to determine whether she was the victim of a genetic or sporadic form of Creutzfeldt-Jakob disease, if the disease may have been caused by the ingestion of meat contaminated by the agent of encephalopathy. bovine spongiform (BSE, also called mad cow disease) or, as in the case of Emilie Jaumain, if accidental occupational exposure can be claimed. Prion diseases are caused by proteins taking an aberrant conformation, which gives them the property of replicating to form aggregates that are deleterious for neurons. There are around 150 cases per year in France, resulting in fatal degeneration of the central nervous system.
Wednesday, July 28, 2021
France issues moratorium on prion research after fatal brain disease strikes two lab workers
Volume 26, Number 8—August 2020
Sporadic Creutzfeldt-Jakob Disease among Physicians, Germany, 1993–2018 high proportion of physicians with sCJD were surgeons
Saturday, January 23, 2021
Improved surveillance of surgical instruments reprocessing following the variant Creutzfeldt-Jakob disease crisis in England: findings from a 3-year survey
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
Variant Creutzfeldt–Jakob disease was identified in a technician who had cut her thumb while handling brain sections of mice infected with adapted BSE 7.5 years earlier. The long incubation period was similar to that of the transfusion-transmitted form of the disease.
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
TO THE EDITOR:
We report a case of variant Creutzfeldt–Jakob disease (CJD) that was plausibly related to accidental occupational exposure in a technician who had handled murine samples contaminated with the agent that causes bovine spongiform encephalopathy (BSE) 7.5 years earlier.
In May 2010, when the patient was 24 years of age, she worked in a prion research laboratory, where she handled frozen sections of brain of transgenic mice that overexpressed the human prion protein with methionine at codon 129. The mice had been infected with a sheep-adapted form of BSE. During this process, she stabbed her thumb through a double pair of latex gloves with the sharp ends of a curved forceps used to handle the samples. Bleeding was noted at the puncture site.
In November 2017, she began having burning pain in the right shoulder and neck. The pain worsened and spread to the right half of her body during the following 6 months. In November 2018, an examination of a sample of cerebrospinal fluid (CSF) obtained from the patient was normal. Magnetic resonance imaging (MRI) of the brain showed a slight increase in the fluid-attenuated inversion recovery (FLAIR) signal in the caudates and thalami (Fig. S1A and S1B in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In January 2019, she became depressed and anxious and had memory impairment and visual hallucinations. There was hypertonia on the right side of her body. At that time, an analysis of CSF for 14-3-3 protein was negative. In March 2019, MRI showed an increased FLAIR signal in pulvinar and dorsomedial nuclei of thalami (Fig. S1C through S1E).
Figure 1.
Detection of Abnormal Prion Protein in Biologic Fluid Samples and Postmortem Findings.
The patient was found to be homozygous for methionine at codon 129 of the prion protein gene without mutation. An analysis of a sample of CSF on real-time quaking-induced conversion analysis was negative for a diagnosis of sporadic CJD. However, an analysis of plasma and CSF by means of protein misfolding cyclic amplification was positive for the diagnosis of variant CJD (Figure 1A and 1B). The patient died 19 months after the onset of symptoms. Neuropathological examination confirmed the diagnosis of variant CJD (Figure 1C and 1D). Western blot analysis showed the presence of type 2B protease-resistant prion protein in all sampled brain areas. The clinical characteristics of the patient and the postmortem neuropathological features were similar to those observed in 27 patients with variant CJD who had previously been reported in France.1 (Additional details are provided in the Supplementary Appendix.)
There are two potential explanations for this patient’s condition. Oral transmission from contaminated cattle products cannot be ruled out because the patient was born at the beginning of the French BSE outbreak in cattle. However, the last two patients who had confirmed variant CJD with methionine homozygosity at codon 129 in France and the United Kingdom died in 2014 and 2013, respectively, which makes oral transmission unlikely. In France, the risk of variant CJD in 2019 was negligible or nonexistent in the post-1969 birth cohort.2
Percutaneous exposure to prion-contaminated material is plausible in this patient, since the prion strain that she had handled was consistent with the development of variant CJD.3 The 7.5-year delay between the laboratory accident and her clinical symptoms is congruent with the incubation period in the transfusion-transmitted form of the disease. The ability of this strain to propagate through the peripheral route has been documented, and experimental studies with scrapie strains have shown that scarification and subcutaneous inoculation are effective routes.4,5 The last known Italian patient with variant CJD, who died in 2016, had had occupational contact with BSE-infected brain tissues, although subsequent investigation did not disclose a laboratory accident (Pocchiari M, Italian Registry of CJD: personal communication). Thus, the last two cases of variant CJD outside the United Kingdom have been associated with potential occupational exposure. Such cases highlight the need for improvements in the prevention of transmission of variant CJD and other prions that can affect humans in the laboratory and neurosurgery settings, as outlined in the Supplementary Appendix.
Jean-Philippe Brandel, M.D. Assistance Publique–Hôpitaux de Paris, Paris, France
M. Bustuchina Vlaicu, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Audrey Culeux, B.Sc. INSERM Unité 1127, Paris, France
Maxime Belondrade, M.Sc. Daisy Bougard, Ph.D. Etablissement Français du Sang, Montpellier, France
Katarina Grznarova, Ph.D. Angeline Denouel, M.Sc. INSERM Unité 1127, Paris, France
Isabelle Plu, M.D. Elodie Bouaziz-Amar, Pharm.D., Ph.D. Danielle Seilhean, M.D., Ph.D. Assistance Publique–Hôpitaux de Paris, Paris, France
Michèle Levasseur, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Stéphane Haïk, M.D., Ph.D. INSERM Unité 1127, Paris, France stephane.haik@upmc.fr
Supported by a grant (ANR-10-IAIHU-06) from Programme d’Investissements d’Avenir and Santé Publique France.
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
5 References
July 2, 2020
N Engl J Med 2020; 383:83-85
DOI: 10.1056/NEJMc2000687
Metrics
SUNDAY, JULY 19, 2020
Joseph J. Zubak Orthopaedic surgeon passed away Monday, July 6, 2020, Creutzfeldt-Jakob Disease (CJD)
Friday, January 29, 2021
Scientists identify locations of early prion protein deposition in retina, what if?
FRIDAY, SEPTEMBER 06, 2019
Disinfection of Multi-Use Ocular Equipment for Ophthalmological Procedures: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines
Creutzfeldt Jakob Disease CJD National Prion Disease Pathology Surveillance Center Cases Examined to December 14, 2017
http://creutzfeldt-jakob-disease.blogspot.com/2017/12/creutzfeldt-jakob-disease-cjd-national.html
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Creutzfeldt Jakob Disease CJD TSE Prion Update December 25, 2021
Saturday, December 18, 2021
Direct neural transmission of vCJD/BSE in macaque after finger incision
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Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
Terry S. Singeltary Sr.
