Tuesday, November 26, 2013

Transmission of multiple system atrophy prions to transgenic mice

Transmission of multiple system atrophy prions to transgenic mice

 

Joel C. Wattsa,b, Kurt Gilesa,b, Abby Oehlerc, Lefkos Middletond, David T. Dextere, Steve M. Gentlemane, Stephen J. DeArmonda,c, and Stanley B. Prusinera,b,1 Author Affiliations

 

aInstitute for Neurodegenerative Diseases, and Departments of bNeurology and cPathology, University of California, San Francisco, CA 94143; and dAgeing Research Unit, School of Public Health and eCentre for Neuroinflammation and Neurodegeneration, Department of Medicine, Imperial College, London SW7 2AZ, United Kingdom Contributed by Stanley B. Prusiner, September 30, 2013 (sent for review August 21, 2013)

 

Significance Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by the accumulation of misfolded α-synuclein protein in glial cells within the brain. Transgenic mice expressing mutant α-synuclein that were inoculated with brain homogenate from MSA patients developed clinical, biochemical, and pathological signs of a neurodegenerative disease, indicating that MSA is transmissible under certain conditions. This transmissibility is reminiscent of the human prion disorders, such as Creutzfeldt–Jakob disease, and suggests that MSA is caused by the accumulation of toxic α-synuclein prions in the brain.

 

Abstract

 

Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson’s disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83+/+ mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83+/− mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83+/− mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83+/− mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83+/+ mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.

 

neurodegeneration bioluminescence imaging seeding proteinopathies Footnotes ↵1To whom correspondence should be addressed. E-mail: stanley@ind.ucsf.edu. Author contributions: J.C.W., K.G., and S.B.P. designed research; J.C.W. and A.O. performed research; L.M., D.T.D., and S.M.G. contributed new reagents/analytic tools; J.C.W., K.G., S.J.D., and S.B.P. analyzed data; and J.C.W., K.G., and S.B.P. wrote the paper.

 

The authors declare no conflict of interest.

 

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1318268110/-/DCSupplemental.

 

 


 

 

 

>>Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions.<<<

 

 

Transmission of a neurodegenerative disorder from humans to mice

 

The neurodegenerative disorder known as multiple system atrophy (MSA) is a variant of Parkinson disease (PD) and is characterized by the accumulation of misfolded α-synuclein protein in glial cells of the brain. Joel Watts et al. (pp. 19555–19560) investigated whether α-synuclein behaves like a prion—a protein that adopts alternative conformations that become self-propagating. The authors injected liquefied samples of brain tissue from patients with MSA into transgenic mice that express low levels of a mutant form of human α-synuclein protein. Unlike transgenic mice that express high levels of mutant α-synuclein and begin developing neurologic illness spontaneously at approximately 10 months of age, mice that express low levels of α-synuclein normally remain healthy throughout their lives; however, approximately 90 days after inoculation with brain tissue from patients with MSA, the mice began to exhibit clinical signs of neurologic dysfunction, the authors report. Furthermore, the brains of inoculated mice contained widespread deposits of α-synuclein, similar to the pattern found in the brains of mice that express high levels of mutant α-synuclein; by contrast, no deposits were found in the brains of uninoculated mice or mice inoculated with human brain tissue that did not have neurodegenerative disease. The findings suggest that the α-synuclein deposits that form in the brains of patients with MSA behave like prions and are transmissible under certain circumstances, according to the authors. — N.Z.

 

α-Synuclein deposits in the brainstems of inoculated mice.

 


 

 
 
Saturday, May 25, 2013

 

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

 


 

 

Sunday, February 10, 2013

 

Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

 


 

 

 

Wednesday, May 16, 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
SEE FULL TEXT AND SOURCE REFERENCES ;

Wednesday, May 16, 2012

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Proposal ID: 29403
http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html


 

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

 


 


 

 

Ann N Y Acad Sci. 1982;396:131-43.

 

Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).

 

Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.

 

Abstract

 

Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.

 


 

 

CJD1/9 0185 Ref: 1M51A

 

IN STRICT CONFIDENCE

 

Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

 

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

 

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC. 2. Briefly, the meeting agreed that:

 

i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;

 

ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

 

iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion. 93/01.05/4.1

 


 

 

BSE101/1 0136

 

IN CONFIDENCE

 

5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992

 

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

 

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

 

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible. What are the implications for public health?

 

3. The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

 

92/11.4/1-1 BSE101/1 0137

 

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

 

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2

 


 

 

BSE101/1 0136

 

IN CONFIDENCE

 

CMO

 

From: Dr J S Metters DCMO

 

4 November 1992

 

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

 


 

 

CJD1/9 0185

 

Ref: 1M51A

 

IN STRICT CONFIDENCE

 

From: Dr. A Wight Date: 5 January 1993

 

Copies:

 

Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

 

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

 


 

 

IATROGENIC

 

 

all iatrogenic cjd is, is sporadic CJD, until route and source of the iatrogenic event that took place, is detected, documented, placed in the academic domain as fact, and recorded, which happens very seldom due to a lot of factors, besides the incubation period, and that be mainly industry. kind of like asbestos and tobacco and the industry there from, they knew in the early 1900’s that they both were killing, and they both had long incubation, and somebody chose not to do anything about if for decades and decades. kind of like what we have here with the TSE prion disease. $$$

 

> In 12 of 15 hospitals with neurosurgical incidents, a decision was made to notify patients of their potential exposure.

 

SO, X number of patients, from 3 hospitals, where

 

''exposure to potentially CJD-contaminated instruments ''

 

took place on these patients, the final decision NOT to tell those folks about the potential exposure to the CJD TSE prion

 

insane, thus, the TSE prion agent continues to spread. ...please see further comments here ;

 


 

 

Saturday, November 2, 2013

 

Recommendation of the Swiss Expert Committee for Biosafety on the classification of activities using prion genes and prion protein January 2013

 


 

 

Saturday, November 16, 2013

 

Management of neurosurgical instruments and patients exposed to creutzfeldt-jakob disease 2013 December

 

Infect Control Hosp Epidemiol.

 


 

 

Thursday, November 14, 2013

 

Prion diseases in humans: Oral and dental implications

 


 

 

CJD QUESTIONNAIRE USA

 


 


 

 

CJD VOICE

 


 

 

 

Monday, October 14, 2013

 

Researchers estimate one in 2,000 people in the UK carry variant CJD proteins

 


 

 

 

Tuesday, October 29, 2013

 

VARIANT CJD PRESENTS DIFFERENTLY IN OLDER PATIENTS

 


 

 

 

Wednesday, October 09, 2013

 

*** WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281 in compensation REVISED

 


 

 

 

Thursday, October 10, 2013

 

CJD REPORT 1994 increased risk for consumption of veal and venison and lamb

 


 

 

 

Friday, August 16, 2013

 

*** Creutzfeldt-Jakob disease (CJD) biannual update August 2013 U.K. and Contaminated blood products induce a highly atypical prion disease devoid of PrPres in primates

 


 


WHAT about the sporadic CJD TSE proteins ?

 

WE now know that some cases of sporadic CJD are linked to atypical BSE and atypical Scrapie, so why are not MORE concerned about the sporadic CJD, and all it’s sub-types $$$

 

 

Creutzfeldt-Jakob Disease CJD cases rising North America updated report August 2013

 

*** Creutzfeldt-Jakob Disease CJD cases rising North America with Canada seeing an extreme increase of 48% between 2008 and 2010 ***

 


 

 

 

Sunday, October 13, 2013

 

CJD TSE Prion Disease Cases in Texas by Year, 2003-2012

 


 

 

 

Saturday, November 2, 2013

 

APHIS Finalizes Bovine Import Regulations in Line with International Animal Health Standards while enhancing the spread of BSE TSE prion mad cow type disease around the Globe

 


 

 

Monday, November 4, 2013

 

*** R-CALF Bullard new BSE rule represents the abrogation of USDA’s responsibility to protect U.S. consumers and the U.S. cattle herd from the introduction of foreign animal disease

 


 

 

 

*** Saturday, November 2, 2013 ***

 

Exploring the risks of a putative transmission of BSE to new species

 


 

 

 

PRIONOPATHY OR PRIONOBALONEY $$$

 

 


 

 


 

 


 

 


 

 


 

 


 

 


 

 


 

 


 

 


 

 


 

 

 

layperson

 

MOM DOD 12/14/97 confirm ‘hvCJD’ just made a promise to mom, NEVER FORGET! and never let them forget. ...

 

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518 flounder9@verizon.net

 

 

 

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