Saturday, June 18, 2011

Self-propagation and transmission of misfolded mutant SOD1 Prion or Prion-like phenomenon?

Self-propagation and transmission of misfolded mutant SOD1 Prion or Prion-like phenomenon?

Christian Münch and Anne Bertolotti* MRC Laboratory of Molecular Biology; Cambridge, England UK

*Correspondence to: Anne Bertolotti; Email: Submitted: 03/21/11; Accepted: 03/22/11 DOI: 10.4161/cc.10.11.15560 Comment on: Münch C, et al. Proc Natl Acad Sci USA 2011; 108:3548–53.

The hallmark of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS), a common and inevitably fatal motor neuron disease, is the presence of proteinaceous deposits in motor neurons. Mutations in the gene encoding the abundantly expressed cytosolic superoxide dismutase- 1 (SOD1) cause aggregation of the protein in some familial forms of the disease.1 While it is clear that misfolding of mutant SOD1 is central to the disease and somehow leads to the degeneration of motor neurons, what elicits aggregation of mutant SOD1 in ALS is unknown. ALS has an adult onset and is rapidly progressive. Likewise, both the deposition of SOD1 aggregates and the appearance of symptoms are progressive in mouse models of ALS.2 Curiously, just like in motor neurons prior to the onset of the disease, SOD1 mutants do not spontaneously form the disease-characteristic deposits in cell culture.2

In a study recently published in PNAS,3 we report that exogenous aggregates prepared from highly purified recombinant SOD1 protein, penetrate inside cells with a surprising efficiency. Like some viruses, SOD1 aggregates use macropinocytosis to enter cells and then rapidly escape this compartment to reach the cytosol. Just like the disease deposits, the internalized SOD1 aggregates are ubiquitinated. Once they have penetrated inside the cytosol, mutant SOD1 aggregates convert the otherwise soluble, intracellular protein to their aberrant conformation.

This is a point of no return. The newly synthetized mutant SOD1 proteins are inevitably corrupted by the internalized aggregates. Furthermore, aggregates are continuously released by cells and taken up by neighbouring cells, hence endlessly continuing this vicious cycle: penetration of aggregates into cells, seeding aggregation of the cellular, normally soluble, homologous protein and transmission of the misfolding pathology to neighbouring cells. Once induced by very small amounts of exogenous seeds, mutant SOD1 aggregation is a self-propagating* phenotype that stably persists in dividing cells, long after the disappearance of the seeds. Thus, mutant SOD1 is the second mammalian protein to fully recapitulate, in cells, the cycle of events characteristic of prions.

Prion disorders such as, Bovine Spongiform Encephalopathy (BSE), scrapie in sheep and Creutzfeld-Jakob disease in human are infectious diseases caused by the aggregated form of the prion protein, PrPSc, which endlessly self-propagate by imposing its altered conformation to the cellular protein PrPC.4 Like the prion, mutant SOD1 aggregates can infect cells: penetrate inside cells, seed aggregation of the homologous protein and replicate.3 Similar to the scrapie agent, mutant SOD1 aggregates display hydrophobic surfaces,5,6 a feature that may underlie their ability to cross cellular membranes. However, unlike prions, there is no evidence that SOD1 aggregates could be transmitted between individuals. The prion realm is not restricted to metazoans and is not necessarily associated with fears of epidemics. A few unrelated yeast prion proteins can adopt self-propagating conformations, responsible for a non-mendelian, cytoplasmic, “proteinonly” mode of inheritance.7 Mutant SOD1 displays the defining properties of a prion, according to the definition proposed by Reed Wickner: “any protein that indefinitely propagates an altered form of itself and is transmissible”.8

Can there be more human prions? Recent studies have revealed that the misfolding pathology characteristic of Alzheimer, Parkinson and Huntington disease can be transmitted experimentally in animal or cellular models (reviewed in ref. 9). These observations are reminiscent of the seeding property of prions and have led to the proposal that misfolding diseases could all be prion-like disorders. However, it remains to be established whether the misfolded proteins associated with Alzheimer, Parkinson and Huntington disease have the ability to self-propagate a change in their conformation in the absence of exogenous seeds, like prions. Further investigations will help defining a clearer distinction between prion and prion-like phenomena.

Note *Self-propagation indicates that the protein indefinitely replicates its altered conformation.

Einstein once said, 'The definition of insanity is doing the same thing over and over again and expecting different results.' re-transmission studies on TSE's...TSS

CJD1/9 0185

Ref: 1M51A


Dr McGovern From: Dr A Wight

Date: 5 January 1993

Copies: Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray


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.


BSE101/1 0136


5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992


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.


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



iatrogenic ???

Wednesday, April 27, 2011


what are they going to do with all us baby boomers by 2050 where an estimated 13.5 million Americans will be stricken with Alzheimer's, up from 5 million plus ? what about the non paid caregivers of these Alzheimer's figures, where by 2050, these figures for caregivers will rise as well, to some 20 million, if we are all still here ? sadly, to add to all this misery, the price of poker is going up too. i apologize for my mood, but i am mad about all these cuts. they have cut funding for prion disease to ZERO DOLLARS!

All Other Emerging and Zoonotic Infectious Diseases CDC's FY 2012 request of $52,658,000 for all other emerging and zoonotic infectious disease activities is a decrease of $13,607,000 below the FY 2010 level, which includes the elimination of Prion activities ($5,473,000), a reduction for other cross-cutting infectious disease activities, and administrative savings. These funds support a range of critical emerging and zoonotic infectious disease programs such Lyme Disease, Chronic Fatigue Syndrome, and Special Pathogens, as well as other activities described below.

what is Alzheimer's anyway ?

strictly NOT private and confidential $$$

Saturday, January 22, 2011

Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011

Friday, September 3, 2010

Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE

Thursday, December 23, 2010

Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom

Saturday, March 22, 2008

10 Million Baby Boomers to have Alzheimer's in the coming decades


Alzheimer’s disease is the seventh leading cause of all deaths in the United States and the fifth leading cause of death in Americans older than the age of 65 years. More than 5 million Americans are estimated to have Alzheimer’s disease. Every 71 seconds someone in America develops Alzheimer’s disease; by 2050 it is expected to occur every 33 seconds. During the coming decades, baby boomers are projected to add 10 million people to these numbers. By 2050, the incidence of Alzheimer’s disease is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million persons. Significant cost implications related to Alzheimer’s disease and other dementias include an estimated $148 billion annually in direct (Medicare/Medicaid) and indirect (eg, caregiver lost wages and out-of-pocket expenses, decreased business productivity) costs. Not included in these figures are the estimated 10 million caregivers who annually provide $89 billion in unpaid services to individuals with Alzheimer’s disease.


see full text and more ;

Wednesday, January 5, 2011



David W. Colby1,* and Stanley B. Prusiner1,2

----- Original Message -----

From: David Colby


Cc: stanley@XXXXXXXX

Sent: Tuesday, March 01, 2011 8:25 AM

Subject: Re: FW: re-Prions David W. Colby1,* and Stanley B. Prusiner1,2 + Author Affiliations

Dear Terry Singeltary,

Thank you for your correspondence regarding the review article Stanley Prusiner and I recently wrote for Cold Spring Harbor Perspectives. Dr. Prusiner asked that I reply to your message due to his busy schedule. We agree that the transmission of CWD prions to beef livestock would be a troubling development and assessing that risk is important. In our article, we cite a peer-reviewed publication reporting confirmed cases of laboratory transmission based on stringent criteria. The less stringent criteria for transmission described in the abstract you refer to lead to the discrepancy between your numbers and ours and thus the interpretation of the transmission rate. We stand by our assessment of the literature--namely that the transmission rate of CWD to bovines appears relatively low, but we recognize that even a low transmission rate could have important implications for public health and we thank you for bringing attention to this matter.

Warm Regards, David Colby


David Colby, PhDAssistant ProfessorDepartment of Chemical EngineeringUniversity of Delaware



CWD to cattle figures CORRECTION


I believe the statement and quote below is incorrect ;

"CWD has been transmitted to cattle after intracerebral inoculation, although the infection rate was low (4 of 13 animals [Hamir et al. 2001]). This finding raised concerns that CWD prions might be transmitted to cattle grazing in contaminated pastures."

Please see ;

Within 26 months post inoculation, 12 inoculated animals had lost weight, revealed abnormal clinical signs, and were euthanatized. Laboratory tests revealed the presence of a unique pattern of the disease agent in tissues of these animals. These findings demonstrate that when CWD is directly inoculated into the brain of cattle, 86% of inoculated cattle develop clinical signs of the disease.

"although the infection rate was low (4 of 13 animals [Hamir et al. 2001])."

shouldn't this be corrected, 86% is NOT a low rate. ...

kindest regards,

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518

Thank you!

Thanks so much for your updates/comments. We intend to publish as rapidly as possible all updates/comments that contribute substantially to the topic under discussion.

re-Prions David W. Colby1,* and Stanley B. Prusiner1,2 + Author Affiliations

1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California 94143 2Department of Neurology, University of California, San Francisco, San Francisco, California 94143 Correspondence:

snip...full text ;

Wednesday, January 5, 2011


David W. Colby1,* and Stanley B. Prusiner1,2

Saturday, March 19, 2011

Familial prion disease with alzheimer disease-like tau pathology and clinical phenotype

Tuesday, June 14, 2011

Clinical research in CJD at a U.S. clinical prion research center: CJD Quinacrine Study results and improved diagnosis of prion disease


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