Monday, June 29, 2009

Beyond the prion principle

News and Views Nature 459, 924-925 (18 June 2009) doi:10.1038/459924a; Published online 17 June 2009


Beyond the prion principle

Adriano Aguzzi

It seems that many misfolded proteins can act like prions — spreading disease by imparting their misshapen structure to normal cellular counterparts. But how common are bona fide prions really?

The protein-only hypothesis of prion propagation is steadily gaining ground. First envisaged by John Stanley Griffith1 and later formalized by Stanley Prusiner2, this theory proposes the existence of an infectious agent composed solely of protein. Three reports, two in Nature Cell Biology3,4 and one in The Journal of Cell Biology5, now contend that, far from being confined to the rare prion diseases, prion-like transmission of altered proteins may occur in several human diseases of the brain and other organs.

Prions are now accepted as causing the transmissible spongiform encephalopathies, which include scrapie in sheep, bovine spongiform encephalopathy (BSE, or mad cow disease) and its human variant Creutzfeldt–Jakob disease. The infectious prion particle is made up of PrPSc, a misfolded and aggregated version of a normal protein known as PrPC. Like the growth of crystals, PrPSc propagates by recruiting monomeric PrPC into its aggregates — a process that has been replicated in vitro6 and in transgenic mice7. The breakage of PrPSc aggregates represents the actual replicative event, as it multiplies the number of active seeds8.

Apart from prion diseases, the misfolding and aggregation of proteins into various harmful forms, which are collectively known as amyloid, causes a range of diseases of the nervous system and other organs. The clinical characteristics of amyloidoses, however, gave little reason to suspect a relationship to prion diseases. Hints of prion-like behaviour in amyloid have emerged from studies of Alzheimer’s disease and Parkinson’s disease. Alzheimer’s disease had been suspected to be transmissible for some time: an early report9 of disease transmission to hamsters through white blood cells from people with Alzheimer’s disease caused great consternation, but was never reproduced. Much more tantalizing evidence came from the discovery10,11 that aggregates of the amyloid-â (Aâ) peptide found in the brain of people with Alzheimer’s disease could be transmitted to the brain of mice engineered to produce large amounts of the Aâ precursor protein APP. Another study12 has shown that healthy tissue grafted into the brain of people with Parkinson’s disease acquires intracellular Lewy bodies — aggregates of the Parkinson’s disease-associated protein á-synuclein. This suggests prion-like transmission of diseased protein from the recipient’s brain to the grafted cells.

These findings10–12 raise a provocative question. If protein aggregation depends on the introduction of ‘seeds’ and on the availability of the monomeric precursor, and if, as has been suggested13, amyloid represents the primordial state of all proteins, wouldn’t all proteins — under appropriate conditions — behave like prions in the presence of sufficient precursor? Acceptance of this concept is gaining momentum. For one thing, an increasing wealth of traits is being found in yeast, fungi and bacteria that can best be explained as prion-like phenomena (see table). And now, Ren and colleagues3 provide evidence for prion-like spread of polyglutamine (polyQ)- containing protein aggregates, which are similar to the aggregates found in Huntington’s disease. They show that polyQ aggregates can be taken up from the outside by mammalian cells. Once in the cytosol, the polyQ aggregates can grow by recruiting endogenous polyQ. Clavaguera et al.4 report similar findings in a mouse model of tauopathy, a neurodegenerative disease caused by intraneuronal aggregation of the microtubule-associated tau protein. Injection of mutant human tau into the brain of mice overexpressing normal human tau transmitted tauopathy, with intracellular aggregation of previously normal tau and spread of aggregates to neighbouring regions of the brain. Notably, full-blown tauopathy was not induced in mice that did not express human tau. Assuming that tau pathology wasn’t elicited by some indirect pathway (some mice overexpressing mutated human tau develop protein tangles even when exposed to un related amyloid aggregates14), this sequence of events is reminiscent of prions. Finally, Frost and colleagues5 show that extracellular tau aggregates can be taken up by cells in culture. Hence, tau can attack and penetrate cells from the outside, sporting predatory behaviour akin to that of prions.

Yet there is one crucial difference between actual prion diseases and diseases caused by other prion-like proteins (let’s call them prionoids) described so far (see table). The behaviour of prions is entirely comparable to that of any other infectious agent: for instance, prions are transmissible between individuals and often across species, and can be assayed with classic microbiological techniques, including titration by bioassay. Accordingly, prion diseases were long thought to be caused by viruses, and BSE created a worldwide panic similar to that currently being provoked by influenza. By contrast, although prionoids can ‘infect’ neighbouring molecules and sometimes even neighbouring cells, they do not spread within communities or cause epidemics such as those seen with BSE.

So, should any amyloid deserve an upgrade to a bone fide prion status? Currently, amyloid A (AA) amyloidosis may be the most promising candidate for a truly infectious disease caused by a self-propagating protein other than PrPSc. AA amyloid consists of orderly aggregated fragments of the SAA protein, and its deposition damages many organs of the body. Seeds of AA amyloid can be excreted in faeces15, and can induce amyloidosis if taken up orally (at least in geese)16. Also, AA amyloid may be transmitted between mice by transfusion of white blood cells17. So, like entero viruses and, perhaps, sheep scrapie prions, AA amyloid seems to display all the elements of a complete infectious life cycle, including uptake, replication and release from its host.

There are intriguing evolutionary implications to the above findings. If prionoids are ubiquitous, why didn’t evolution erect barriers to their pervasiveness? Maybe it is because the molecular transmissibility of aggregated states can sometimes be useful. Indeed, aggregation of the Sup35 protein, which leads to a prion-like phenomenon in yeast, may promote evolutionary adaptation by allowing yeast cells to temporarily activate DNA sequences that are normally untranslated18. Mammals have developed receptors for aggregates, and ironically PrPC may be one of them19, although these receptors have not been reported to mediate protective functions. Therefore, we shouldn’t be shocked if instances of beneficial prionoids emerge in mammals as well. ¦

Adriano Aguzzi is at the Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland. e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000029/!

1. Griffith, J. S. Nature 215, 1043–1044 (1967). 2. Prusiner, S. B. Science 216, 136–144 (1982). 3. Ren, P.-H. et al. Nature Cell Biol. 11, 219–225 (2009). 4. Clavaguera, F. et al. Nature Cell Biol. doi:10.1038/ncb1901 (2009). 5. Frost, B., Jacks, R. L. & Diamond, M. I. J. Biol. Chem. 284, 12845–12852 (2009). 6. Castilla, J., Saá, P., Hetz, C. & Soto, C. Cell 121, 195–206 (2005). 7. Sigurdson, C. J. et al. Proc. Natl Acad. Sci. USA 106, 304–309 (2009). 8. Aguzzi, A. & Polymenidou, M. Cell 116, 313–327 (2004). 9. Manuelidis, E. E. et al. Proc. Natl Acad. Sci. USA 85, 4898–4901 (1988). 10. Kane, M. D. et al. J. Neurosci. 20, 3606–3611 (2000). 11. Meyer-Luehmann, M. et al. Science 313, 1781–1784 (2006). 12. Li, J.-Y. et al. Nature Med. 14, 501–503 (2008). 13. Chiti, F. & Dobson, C. M. Annu. Rev. Biochem. 75, 333–366 (2006). 14. GÖtz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Science 293, 1491–1495 (2001). 15. Zhang, B. et al. Proc. Natl Acad. Sci. USA 105, 7263–7268 (2008). 16. Solomon, A. et al. Proc. Natl Acad. Sci. USA 104, 10998–11001 (2007). 17. Sponarova, J., NystrÖm, S. N. & Westermark, G. T. PLoS ONE 3, e3308 (2008). 18. True, H. L. & Lindquist, S. L. Nature 407, 477–483 (2000). 19. Laurén, J. et al. Nature 457, 1128–1132 (2009). PRIONS AND POTENTIAL PRIONOIDS Disease Protein Molecular transmissibility Infectious life cycle Prion diseases PrPSc Yes Yes Alzheimer’s disease Amyloid-ß Yes Not shown Tauopathies Tau Yes Not shown Parkinson’s disease a-Synuclein Host-to-graft Not shown AA amyloidosis Amyloid A Yes Possible Huntington’s disease Polyglutamine Yes Not shown Phenotype Protein Molecular transmissibility Infectious life cycle Suppressed translational termination (yeast) Sup35 Yes Not shown Heterokaryon incompatibility (filamentous fungi) Het-s Yes Not shown Biofilm promotion (bacteria) CsgA Yes Not shown In humans and animals, infectious prion diseases are caused by PrPSc, which spreads by recruiting its monomeric precursor PrPC into aggregates. Aggregates then multiply by breakage, a process that is termed molecular transmissibility. Other proteins involved in disease and in phenotypes of fungi and bacteria, can also undergo self-sustaining aggregation, but none of these ‘prionoid’ proteins behaves like typical infectious agents, nor do any of them enact a complete infectious life cycle — with the possible exception of AA amyloid. Correction In the News & Views article “Immunology: Immunity’s ancient arms” by Gary W. Litman and John P. Cannon (Nature 459, 784–786; 2009), the name of the fi rst author of the Nature paper under discussion was misspelt. The author’s name is P. Guo, not Gou as published.

© 2009 Macmillan Publishers Limited. All rights reserved

Thursday, February 26, 2009

'Harmless' prion protein linked to Alzheimer's disease Non-infectious form of prion protein could cause brain degeneration ???



CJD1/9 0185

Ref: 1M51A



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 neurodegeneradve 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.


Regarding Alzheimer's disease

(note the substantial increase on a yearly basis)


The pathogenesis of these diseases was compared to Alzheimer's disease at a molecular level...


And NONE of this is relevant to BSE?

There is also the matter whether the spectrum of ''prion disease'' is wider than that recognized at present.


BSE101/1 0136


5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992


also, see the increase of Alzheimer's from 1981 to 1986

Tuesday, August 26, 2008

Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3

see full text ;

Alzheimer's and CJD

Saturday, March 22, 2008

10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures

re-Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Elsevier Editorial System(tm) for The Lancet Infectious Diseases Manuscript Draft Manuscript Number:

Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory

Article Type: Personal View Corresponding

snip...see full text 31 pages ;

Tuesday, August 26, 2008

Alzheimer's Transmission of AA-amyloidosis: Similarities with Prion Disorders NEUROPRION 2007 FC4.3

Sunday, June 7, 2009


Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734.

Full Text

Tue, 13 Feb 2001 JAMA Vol. 285 No. 6, February 14, 2001 Letters

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

To the Editor:

In their Research Letter in JAMA. 2000;284:2322-2323, 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

To the Editor:

At the time of my mother's death, various diagnoses were advanced such as "rapid progressive Alzheimer disease," psychosis, and dementia. Had I not persisted and personally sought and arranged a brain autopsy, her death certificate would have read cardiac failure and not CJD.

Through CJD Voice1 I have corresponded with hundreds of grief-stricken families who are so devastated by this horrific disease that brain autopsy is the furthest thing from their minds. In my experience, very few physicians suggest it to the family. After the death and when families reflect that they never were sure what killed their loved one it is too late to find the true cause of death. In the years since my mother died I think that the increasing awareness of the nature of CJD has only resulted in fewer pathologists being willing to perform an autopsy in a suspected case of CJD.

People with CJD may die with incorrect diagnoses of dementia, psychosis, Alzheimer disease, and myriad other neurological diseases. The true cause of death will only be known if brain autopsies are suggested to the families. Too often the physician's comment is, "Well, it could be CJD but that is so rare it isn't likely."

Until CJD is required to be reported to state health departments, as other diseases are, there will be no accurate count of CJD deaths in the United States and thus no way to know if the number of deaths is decreasing, stable, or increasing as it has recently in the United Kingdom.

Dorothy E. Kraemer Stillwater, Okla

In Reply:

Mr Singeltary and Ms Kraemer express an underlying concern that our recently reported mortality surveillance estimate of about 1 CJD case per million population per year in the United States since 1985 may greatly underestimate the true incidence of this disease. Based on evidence from epidemiologic investigations both within and outside the United States, we believe that these national estimates are reasonably accurate.

Even during the 1990s in the United Kingdom, where much attention and public health resources have been devoted to prion disease surveillance, the reported incidence of classic CJD is similar to that reported in the United States.

In addition, in 1996, active US surveillance for CJD and new variant (nv) CJD in 5 sites detected no evidence of the occurrence of nvCJD and showed that 86% of the CJD cases in these sites were identifiable through routinely collected mortality data.

Our report provides additional evidence against the occurrence of nvCJD in the United States based on national mortality data analyses and enhanced surveillance. It specifically mentions a new center for improved pathology surveillance. We hope that the described enhancements along with the observations of Singeltary and Kraemer will encourage medical care providers to suggest brain autopsies for more suspected CJD cases to facilitate the identification of potentially misdiagnosed CJD cases and to help monitor the possible occurrence of nvCJD.

Creutzfeldt-Jakob disease is not on the list of nationally notifiable diseases. In those states where surveillance personnel indicate that making this disease officially notifiable would meaningfully facilitate collection of data that are needed to monitor the incidence of CJD and nvCJD, including the obtaining of brain autopsy results, we encourage such a change. However, adding CJD to the notifiable diseases surveillance system may lead to potentially wasteful, duplicative reporting because the vast majority of the diagnosed cases would also be reported through the mortality surveillance system.

Furthermore, making CJD a notifiable disease may not necessarily help identify undiagnosed CJD cases. The unique characteristics of CJD make mortality data a useful surrogate for ongoing surveillance. Unlike many other neurologic diseases, CJD is invariably fatal and in most cases rapidly progressive and distinguishable clinically from other neurologic diseases.

Because CJD is least accurately diagnosed early in the course of the illness, notifiable disease surveillance of CJD could be less accurate than mortality surveillance of CJD. In addition, because death as a condition is more completely and consistently reported, mortality surveillance has the advantage of being ongoing and readily available.

The absence of CJD and nvCJD from the list of nationally notifiable diseases should not be interpreted to mean that they are not important to public health; this list does not include all such diseases. We encourage medical caregivers to report to or consult with appropriate public health authorities about any diagnosed case of a transmissible disease for which a special public health response may be needed, including nvCJD, and any patient in whom iatrogenic transmission of CJD may be suspected.

Robert V. Gibbons, MD, MPH Robert C. Holman, MS Ermias D. Belay, MD Lawrence B. Schonberger, MD, MPH Division of Viral and Rickettsial Diseases National Center for Infectious Diseases Centers for Disease Control and Prevention Atlanta, Ga

Full Text Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734.


The Pathological Protein

Publisher Springer New York DOI 10.1007/b97488 Copyright 2003 ISBN 978-0-387-95508-7 (Print) 978-0-387-21755-0 (Online) DOI 10.1007/0-387-21755-X_14 Pages 223-237 Subject Collection Humanities, Social Sciences and Law SpringerLink

Laying Odds


Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.


The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.


Monday, April 20, 2009

National Prion Disease Pathology Surveillance Center Cases Examined1 (December 31, 2008)

April 20, 2009

National Prion Disease Pathology Surveillance Center Cases Examined1 (December 31, 2008)

National Prion Disease Pathology Surveillance Center Cases Examined1

(December 31, 2008)

Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD

1996 & earlier 42 32 28 4 0 0

1997 115 68 59 9 0 0

1998 93 53 45 7 1 0

1999 115 69 61 8 0 0

2000 151 103 89 14 0 0

2001 210 118 108 9 0 0

2002 258 147 123 22 2 0

2003 273 176 135 41 0 0

2004 335 184 162 21 0 13

2005 346 193 154 38 1 0

2006 380 192 159 32 0 14

2007 370 212 185 26 0 0

2008 383 228 182 23 0 0

TOTAL 30715 17756 1490 254 4 2

1 Listed based on the year of death or, if not available, on year of referral; 2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted; 3 Disease acquired in the United Kingdom; 4 Disease acquired in Saudi Arabia; 5 Includes 20 cases in which the diagnosis is pending, and 17 inconclusive cases; 6 Includes 25 cases with type determination pending in which the diagnosis of vCJD has been excluded.

Rev 2/13/09 National

*5 Includes 20 cases in which the diagnosis is pending, and 17 inconclusive cases; *6 Includes 25 cases with type determination pending in which the diagnosis of vCJD has been excluded.


it would be interesting to know what year these atypical cases occurred, as opposed to lumping them in with the totals only.

are they accumulating ?

did they occur in one year, two years, same state, same city ?

location would be very interesting ?

age group ?

sex ?

how was it determined that nvCJD was ruled out ?

from 1997, the year i started dealing with this nightmare, there were 28 cases (per this report), up until 2007 where the total was 185 cases (per this report), and to date 2008 is at 182. a staggering increase in my opinion, for something that just happens spontaneously as some would have us believe. i don't believe it, not in 85%+ of all sporadic CJD cases. actually, i do not believe yet that anyone has proven that any of the sporadic CJD cases have been proven to be a spontaneous misfolding of a protein. there are many potential routes and sources for the sporadic CJD's. ...TSS

please see full text here ;

Rare BSE mutation raises concerns over risks to public health

SIR - Atypical forms (known as H- and L-type) of bovine spongiform encephalopathy (BSE) have recently appeared in several European countries as well as in Japan, Canada and the United States. This raises the unwelcome possibility that variant Creutzfeldt-Jakob disease (vCJD) could increase in the human population. Of the atypical BSE cases tested so far, a mutation in the prion protein gene (PRNP) has been detected in just one, a cow in Alabama with BSE; her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS Pathog. 4, e1000156; 2008). This raises the possibility that the disease could occasionally be genetic in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the UK epidemic had most likely originated from such a mutation and argued against the scrapierelated assumption. Such rare potential pathogenic PRNP mutations could occur in countries at present considered to be free of BSE, such as Australia and New Zealand. So it is important to maintain strict surveillance for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many countries still feed ruminant proteins to pigs). Removal of specified risk material, such as brain and spinal cord, from cattle at slaughter prevents infected material from entering the human food chain. Routine genetic screening of cattle for PRNP mutations, which is now available, could provide additional data on the risk to the public. Because the point mutation identified in the Alabama animals is identical to that responsible for the commonest type of familial (genetic) CJD in humans, it is possible that the resulting infective prion protein might cross the bovine-human species barrier more easily. Patients with vCJD continue to be identified. The fact that this is happening less often should not lead to relaxation of the controls necessary to prevent future outbreaks. Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000029/! Jürgen A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier Hall, Manhattan, Kansas 66506-5601, USA

NATUREVol 45726 February 2009

see full text ;

Monday, May 11, 2009

Rare BSE mutation raises concerns over risks to public health

Saturday, March 22, 2008

10 Million Baby Boomers to have Alzheimer's in the coming decades 2008 Alzheimer's disease facts and figures


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