Posts Tagged ‘Creutzfeld-Jakob’

Prions: infectious states of protein folding

6 November, 2010

In my teaching of virology, I have always covered “virus-like entities” as well – which includes satellite viruses, plasmids, viroids, satellite nucleic acids – and prions.  Pronounced PREE-ONS, according to Stanley Prusiner, the man who got a Nobel Prize in 1997 for describing them, who told me this in a bus in 1987 coming back from an especially well lubricated International Congress of Virology dinner in Edmonton, Alberta.

So it may or may not have been remembered as well as it could have been.  Especially as I vaguely recall singing him and Ted Diener – of viroid fame – a song about salesmen, and getting 25c in my hat for my trouble.

In any case, the inclusion of prions as being virus-like is based more on their ability to cause disease, and be infectious, than on their similarity to viruses – because there really is no similarity at all.

Consider: viruses are obligate intracellular parasites, which use particles assembled inside cells to transport their nucleic acid genomes around in order to establish new infections.  Satellite viruses – of which there are both DNA and RNA varieties – are the same, except for needing some functions provided in trans by an autonomous virus.  Satellite nucleic acids – again, both RNA and DNA – require a helper virus and do not encode their own coat proteins, and sometimes encode no protein at all.  Viroids are single-strand circular RNAs which effectively code for nothing but their own secondary and tertiary structures, which in turn serve to co-opt the host RNA pol II – a transcription polymerase – to replicate their genomes via a rolling-circle mechanism.  And sometimes also encode “ribozyme” enzyme functions, such as ligase/RNAse.

Prions, on the other hand, are proteins encoded for and made by normal cells – only eukaryotes as far as we know – which have suffered a structural conversion or misfolding into a state which allows them to act as templates for the structural conversion of normally folded proteins of the same or similar sequence.  Moreover, the way in which the aberrant folding occurs – to a variety of related but distinct structures – may define the type of disease and its manifestation.

In other words, prions are nothing more or less than “an infectious state of protein folding which leads to pathology“.

Transmission of BSE prions to humans. Copyright Russell Kightley Media

I have done a number of pieces on prions over the last couple of years, largely due to the morbid curiosity engendered by the Great British Beef Scandal of years gone by, when it was shown that meat from a significant number of cattle suffering from bovine spongiform encephalopathy or BSE, aka Mad Cow Disease, had entered the human food chain in the UK – and several other places.  What resulted was a fatal infectious disease, known as new variant Creutzfeld-Jakob disease (vCJD) to distinguish it from the classical (largely sporadic, or genetic) CJD.  There was a well-justified fear at the time that vCJD cases would reach epidemic proportions – but this has not happened, and the number of cases reached a quite low peak and has been decreasing for some time.

I have covered prions again today because of a ProMED post I have just received, which covers the present state of human prion diseases very nicely, and which I reproduce below.



ProMED-mail post <>

ProMED-mail is a program of the International Society for Infectious Diseases <>

[With the continuing decline of the number of cases in the human  population of variant Creutzfeldt-Jakob disease — abbreviated  previously as vCJD or CJD (new var.) in ProMED-mail — it has been  decided to broaden the scope of the occasional ProMED-mail updates to  include other prion-related diseases. In addition to vCJD, data on  other forms of CJD: sporadic, iatrogenic, familial, and GSS  (Gerstmann-Straussler-Scheinker disease) are included also since they  may have some relevance to the incidence and etiology of vCJD. – Mod.CP]

In this update:

[1] UK: National CJD Surveillance Unit – monthly statistics as of Mon  1 Nov 2010 – no new vCJD cases

[2] France: Institut de Veille Sanitaire – monthly statistics as of  Fri 29 Oct 2010 – no new vCJD cases

[3] USA: National Prion Disease Pathology Surveillance Center – data  not updated since 31 Jul 2010, no indigenous vCJD

[4] Prion disease susceptibility  ******

[1] UK: National CJD Surveillance Unit – monthly statistics as of Mon  1 Nov 2010 – no new vCJD cases

Date: Mon 1 Nov 2010

Source: UK National CJD Surveillance Unit, monthly statistics [edited] <>

The number of deaths due to definite or probable vCJD cases remains  170. A total of 4 definite/probable patients are still alive so the  total number of definite or probable vCJD cases remains 174.  Although 3 new deaths due to vCJD were recorded in 2009 and now 3  deaths in 2010 so far, the overall picture is still consistent with  the view that the vCJD outbreak in the UK is in decline, albeit now  with a pronounced tail. The 1st cases were observed in 1995, and the  peak number of deaths was 28 in the year 2000, followed by 20 in  2001, 17 in 2002, 18 in 2003, 9 in 2004, 5 in 2005, 5 in 2006, 5 in  2007, one in 2008, 3 in 2009, and now 3 so far in 2010.  Totals for all types of CJD cases in the UK so far in the year 2010

——————————————————————- During the 1st 10 months of 2010, there have been 126 referrals, 54  fatal cases of sporadic CJD, 3 fatal cases of vCJD, 2 cases of  iatrogenic CJD, 2 cases of familial CJD, and one case of GSS.

— Communicated by: ProMED-mail <>  ******

[2] France: Institut de Veille Sanitaire – monthly statistics as of  Fri 29 Oct 2010 – no new vCJD cases

Date: Fri 5 Nov 2010

Source: IVS – Maladie de Creutzfeldt-Jakob et maladies apparentees [in French, trans. & summ. Mod.CP, edited] <>

During the 1st 10 months of 2010, there were 1332 referrals, 75  confirmed cases of sporadic CJD, 4 cases of familial CJD, and no  cases of iatrogenic CJD or vCJD.  A total of 25 cases of confirmed or probable vCJD have been recorded  in France since records began in 1992. There was 1 case in 1996, 1 in  2000, 1 in 2001, 3 in 2002, 2 in 2004, 6 in 2005, 6 in 2006, 3 in  2007, 2 in 2009, and none so far in 2010.  The 25 confirmed cases comprise 13 females and 12 males. All 25 are  now deceased. Their median age is 37 (between 19 and 58). 7 were  resident in the Ile-de-France and 18 in the provinces. All the  identified cases have been Met-Met homozygotes. No risk factor has  been identified. One of the 25 had made frequent visits to the United  Kingdom, during about 10 years from 1987.

— Communicated by: ProMED-mail <>  ******

[3] USA: National Prion Disease Pathology Surveillance Center – data  not updated since 31 Jul 2010, no indigenous vCJD

Date: Fri 5 Nov 2010

Source: US National Prion Disease Pathology Surveillance Center [edited] <>

No update since 31 Jul 2010.  During the 7 month period 1 Jan 2010 to 31 Jul 2010, there were 204  referrals, 124 of whom were classified as prion disease, comprising  85 cases of sporadic CJD, 20 of familial CJD, and no cases of  iatrogenic CJD or vCJD.  — Communicated by: ProMED-mail <>  ******

[4] Prion disease susceptibility

Date: Mon 1 Nov 2010

Source: Proceedings of the National Academy of Sciences of the USA  (PNAS) [edited] <>

Ref: MQ Khan, B Sweeting, VK Mulligan, et al: Prion disease  susceptibility is affected by beta-structure folding propensity and  local side-chain interactions in PrP. Proc Natl Acad Sci USA 2010  (Epub ahead of print); doi:10.1073/pnas.1005267107

———————————————————————- Abstract ——–

Prion diseases occur when the normally alpha-helical prion protein  (PrP) converts to a pathological beta-structured state with prion  infectivity (PrPSc). Exposure to PrPSc from other mammals can  catalyze this conversion. Evidence from experimental and accidental  transmission of prions suggests that mammals vary in their prion  disease susceptibility: hamsters and mice show relatively high  susceptibility, whereas rabbits, horses, and dogs show low susceptibility.  Using a novel approach to quantify conformational states of PrP by  circular dichroism (CD), we find that prion susceptibility tracks  with the intrinsic propensity of mammalian PrP to convert from the  native, alpha-helical state to a cytotoxic beta-structured state,  which exists in a monomer-octamer equilibrium. It has been  controversial whether beta-structured monomers exist at acidic pH;  sedimentation equilibrium and dual-wavelength CD evidence is  presented for an equilibrium between a beta-structured monomer and  octamer in some acidic pH conditions.  Our X-ray crystallographic structure of rabbit PrP has identified a  key helix-capping motif implicated in the low prion disease  susceptibility of rabbits. Removal of this capping motif increases  the beta-structure folding propensity of rabbit PrP to match that of  PrP from mouse, a species more susceptible to prion disease.  –[my emphasis]

Communicated by: ProMED-mail <>

[This research provides a physical explanation of how changes in the  structure of the prion protein can affect the prion disease  susceptibility of different mammals. – Mod.CP]

This last comment is especially interesting, because it highlights something that has been of interest for some time – as in, how do prions from one species affect another?  In other words, just how transmissible are prion diseases, and in which directions?  And which variants of the gene predispose towards greater or lesser susceptibility?

Food for serious thought, undoubtedly.  But I’m still a meat eater….

Just when you thought it was safe….

12 September, 2010

…to have a hamburger. ProMED, those wonderful people who brought you Ebola case by case, describe a new way to rot your brain. Read on.

New sporadic prion disease
Date: Fri 13 Aug 2010
Source: Science Daily [edited]

BSE Transmission

New sporadic prion protein disease:
variably protease-sensitive prionopathy shares genotype characteristics with Creutzfeldt-Jakob

A new sporadic prion protein disease has been discovered. Variably protease-sensitive prionopathy (VPSPr), as it has been named, is the 2nd type of complete sporadic disease to be identified since Creutzfeldt-Jakob disease (CJD) was reported in the 1920s. The landmark finding from the National Prion Disease Pathology Surveillance Center at Case Western Reserve University is published in the August [2010] issue of Annals of Neurology [see abstract below].

Normally, the human prion protein gene comes in 3 types due to its
capability to encode prion proteins that contain only the amino acid
methionine, commonly identified as M, both methionine and valine, commonly identified as V, or only for the amino acid valine at position 129. Therefore, when it comes to the prion protein gene unaffected people can be identified as 129MM, 129MV or 129VV. Sporadic CJD (sCJD), which is the most common human prion disease, can affect patients who have any one of the 3 types of the prion protein gene.

In 2008, Pierluigi Gambetti and Wen-Quan Zou, with collaborators, reported the discovery of this novel disease, which affected patients who exhibit only one of the 3 types of the prion protein gene. In this follow-up study, they discovered that all 3 genetic groups can be affected also by this novel disease which now joins sCJD in displaying this feature. However, VPSPr is associated with an abnormal prion protein that exhibits characteristics very different from those of sCJD, as well as other prion diseases, suggesting that it may be caused by a different mechanism, perhaps more akin to other neurodegenerative diseases, such as Alzheimer’s disease. This finding may exemplify, for the 1st time, the possibility that the prion protein affects the brain with different mechanisms.

While examining cases received at the National Prion Disease Pathology Surveillance Center where he is the director, Dr Gambetti observed that a subset of cases had clinical and pathological features quite different from those of all known types of human prion diseases. Further, after being tested for prion proteins via the Western blot [technique] — the gold standard of prion disease diagnosis — the cases were negative. Dr Gambetti then collaborated with Dr Zou, associate director at the center, to solve the riddle of a disease that exhibited some features of a prion disease in histopathological examination but was negative using the standard Western blot test.

Dr Zou’s lab performed a full characterization of the disease and discovered that the VPSPr-associated abnormal prion protein formed a ladder-like electrophoretic profile on Western blotting. “When I obtained the 1st Western blot result of these cases with a different antibody against prions, I was surprised that these cases consistently exhibited this particular profile; one that I had never seen in my more than 10 years of work on human prion diseases,” Dr Zou, assistant professor of pathology at Case Western Reserve School of Medicine, recalls. This ladder-like profile is quite distinctive and very different from the profile of common prion diseases. “Discovery of this unique type of prion provides solid evidence that this novel disease may possess a pathogenesis that is different from that of the major prion diseases currently known,” Dr Zou adds.

Despite extensive research, a relatively large group of neurodegenerative diseases associated with dementia remain undefined. Before being discovered and characterized, VPSPr was one of the undefined dementing diseases. The discovery of VPSPr is chipping away at that group. In the 2 years since its discovery, more than 30 cases have been reported.

“If, as the current evidence indicates, the VPSPr mechanism of affecting the brain is different from that of other sporadic prion diseases, such as sCJD, the discovery of VPSPr would also provide the 1st example that the prion protein may spontaneously damage the brain with different mechanisms,” concludes Dr Gambetti, professor of pathology at Case Western Reserve School of Medicine. “This might apply to other dementing illnesses as well, and has implications for the strategies that need to be followed to attain a cure.”

Drs Gambetti and Zou, along with their extensive research team, plan to further characterize the abnormal prion protein associated with VPSPr as well as other important features of the protein, such as the disease’s propensity for transmission upon inoculation and its replication in test tubes. These features in VPSPr will be compared with those of sCJD to obtain a complete picture of how the abnormal prion protein attacks the brain in these 2 diseases.

– — communicated by: ProMED-mail rapporteur Mary Marshall

[The following is the reference for the paper discussed above followed by the authors’ abstract: Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I, et al. Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein. Ann Neurol. 2010 Aug;68(2):162-72. ().

Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio.


Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods: A total of 15 affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with “variably protease- sensitive prionopathy” (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the 2nd sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Straussler-Scheinker disease.

VPSPr is not linked to eating infected meat. However, like CJD, the new condition happens sporadically. It was 1st identified because of the fast-advancing form of dementia seen in those affected. They were also unable to speak or move. But tests for CJD proved negative. Further molecular examination as described above has shown VPSPr was a prion disease, but one which looked very different to those already known. – Mod.CP]

Enough said.  Just more to worry about…B-)