Posts Tagged ‘CJD’

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….