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Author Topic: How are infectious prion diseases, like BSE, transmitted?  (Read 35647 times)

Offline mee

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #50 on: 01/08/2004 02:46:33 »
In mad cow disease, perhaps the prions cause the brains naturally similar proteins to change into the new form because the new form is somehow more efficient to reproduce than the other, natural form. Perhaps it could be the path of least resistance for the brain to produce the protein in the new form. I'm not sure if this will help cure it, but perhaps it could help determine the mechanisms for illness. Please feel free to forward this to anyone who might find this useful.
 

Offline mee

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #51 on: 01/08/2004 03:04:39 »
Perhaps another thing I should have added, was that the prion is perhaps more efficient at replication or certain cellular processes the normal protein used to do but has undesireable side effects in addition to this increase in efficiency.  The increase in efficiency would be a possible reason for the spread of the disease through the brain as the prions are being manufactured faster than the normal proteins.
 

Offline mee

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #52 on: 01/08/2004 03:20:12 »
quote:
Originally posted by Big_Jules

To add another layer to this discussion, there is variation in the sequence of bases in the gene and hence the sequence of amino acids (building blocks) in normal prion protein among any animal species, including us. Such differences also confer a greater disposition to heritable neurodegenerative diseases such as conventional CJD. It appears that certain of these variations make the normal prion protein more or less susceptible to confirmational change induced by the 'rogue' prion protein. Several of these sequences have been identified. Presumably, interaction between key amino acid sequences in the rogue and normal proteins enact the conformational change. As Chris has stated, the beta-sheet conformation appears to be highly resistant to enzymatic digestion, so that enzymatic digestion, specially within neural tissue, is unlikely. With respect to antibodies, one would imagine that the indigenous protein, while changed in shape, would still be recognised as 'self' and not susceptible to immune attack.



If the prion is more resistant to enzymatic digestion, perhaps the protein it replaces is broken down naturally by the system as part of the process of normal cellular function and the prions, being resistant, build up in the brain.  A bit of another angle perhaps.
 

Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #53 on: 02/08/2004 17:53:39 »
Interesting idea, but I don't think there is any evidence to suggest that the prions are synthesised in the abnormal conformation. I think current thinking favours the concept of conversion of globular prions by the abnormal form, rather than the converse.

Chris

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Offline mee

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #54 on: 14/08/2004 16:49:13 »
Chris, could you please explain your position further as it seems confusing to me what you are trying to say.  Are you saying that the prions convert the normal proteins directly?  What would be the mechanism?  If normal and abnormal proteins were placed in a dish together, would they all become abnormal?  I would think a cellular process would be necessary for the conversion.  Why would the abnormal protein be selected for if it is not somehow more efficient to process them?
 

Offline steelgraham

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #55 on: 14/08/2004 17:26:51 »
The up to date position is that 8 patients with four different types of Prion disease are now receiving Pentosan Polysulphate in attempt to arrest or slow down the disease. Pentosan alone is unlikely to cure patients with this group of diseases. However, there is a "glimmer of hope" now that was never there in the past. It is too early to say what the outcome will be in relation to this development. More clinical and scientific work is required. However, the side effects in humans that were feared "have not occurred".
 

Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #56 on: 14/08/2004 18:38:38 »
quote:
Originally posted by mee

Chris, could you please explain your position further as it seems confusing to me what you are trying to say.  Are you saying that the prions convert the normal proteins directly?  What would be the mechanism?  If normal and abnormal proteins were placed in a dish together, would they all become abnormal?  I would think a cellular process would be necessary for the conversion.  Why would the abnormal protein be selected for if it is not somehow more efficient to process them?



Sure. One group (that I know of) have been able to demonstrate conversion of healthy prions (PrPc) to scrapie prions (PrP sc) in a test tube, demonstrating that scrapie prion is necessary and sufficient for abnormal prion propagation. However, precisely how this conversion is achieved is still not understood. In some way the abnormal conformation inflicts itself upon the normal, globular, form of the protein and induces the conformational change that results in a scrapie prion. The newly formed scrapie prion is thence itself able to assimilate / misappropriate other healthy prions and turn them into scrapie forms so that the whole process is like a huge positive feedback loop. This is why these diseases (TSEs) accelerate alarmingly, and patients usually deteriorate quite rapidly, following the onset of symptoms and after a long incubation period.

Chris

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Offline Moka

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #57 on: 06/09/2004 16:32:03 »
Hi, I'm interested in prion's structure. Does anyone know, that the structure of PrPSc has been determined already? Why is it difficult? What hinders the experiments? As far as I know, the sctructure of PrPC is known for years...
 

Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #58 on: 18/09/2004 12:01:12 »
Hi Moka

the structure of PrP is well established and the switch to a pathological (scrapie) form involves a conformational change from a predominantly globular to a beta-pleated sheet architecture.

As such, this fibrous beta-pleated sheet structure is extremely stable and resilient to most degradative mechanisms. It is for this reason that contaminated neurosurgical instruments proved so difficult to disinfect and are now routinely destroyed after a procedure.

Chris

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Offline TomG1987

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #59 on: 18/09/2004 15:07:09 »
So in order for PrPc to be converted to PrPsc the presence of the abnormal PrPsc must be present, but this meant that some radical mutation within the DNA sequence coding for the gene PrPc must take place in order for the inital PrPsc to be present surely? Any websites you may have with links to prion diseases would be most helpfull as I am about to go for my interview at Cambridge University and need to know more about prions.

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Offline Nicky67

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #60 on: 19/09/2004 00:46:52 »
Fascinating thread!

There must be some theories, albeit unproven as yet, as to how the pathological form converts the normal PrP? Does anyone know them?

Is the pathological form entirely a beta-pleated sheet?

Please please anyone who knows any more do explain further! I am ignorant but would love very much to learn!
 

Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #61 on: 20/09/2004 16:09:41 »
No Tom, no change is necessary in the DNA encoding the prion gene for the conversion to take place - otherwise healthy individuals would not be susceptible to BSE. That said, there are certain endogenous forms of prion disease which originate from a PrP gene mutation which makes the switch to a beta-pleated sheet (PrPsc) more favourable. GSS and FFI (fatal familial insomnia) are 2 such examples.

Chris


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Offline TomG1987

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #62 on: 02/10/2004 16:37:47 »
Hm, you misunderstand me chris, i mean how did the initial molecule of PrPsc come into being. Because mutation of dna would cause such a change in PrPc to make it abrnomal, and also paired with the fact that only one in hundreds of billions of PrPc molecules flip spontaneously into PrPsc. So it makes sense some mutugen causes a problem during translation or transcription (more than likely in translation) that would create the first PrPsc molecule. It's the chicken and the egg. But no-one's defined the chicken.

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Offline steelgraham

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #63 on: 03/10/2004 12:10:06 »
Have been reading an interesting book on related matters. As you will know, not everybody supports the Prion Protein only theory.To quote from the late Peter Wildy (Cambridge Uni. 1985):-

The chemical state of the prion
Is the latest genetical try on
It's flaccid and placid
No nucleic acid
Just protein it has to rely on


Any comments?

Graham


 

Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #64 on: 04/10/2004 08:12:50 »
quote:
Originally posted by TomG1987

Hm, you misunderstand me chris, i mean how did the initial molecule of PrPsc come into being. Because mutation of dna would cause such a change in PrPc to make it abrnomal, and also paired with the fact that only one in hundreds of billions of PrPc molecules flip spontaneously into PrPsc. So it makes sense some mutugen causes a problem during translation or transcription (more than likely in translation) that would create the first PrPsc molecule.


Hi Tom,

Not quite. You are assuming that something is translated into the state in which it is destined to remain. You are correct when you say one in hundreds of billions of Prp molecules will flip spontaneously - that's why it takes a lifetime of rolling the dice to eventually end up with 1 person in a million developing sporadic CJD. It's a stochastic process that happens at very low frequency, hence it usually takes over 60 years. Perhaps as we see humans living longer we'll begin to disclose more cases in old age.

However, there are a number of PrP mutations which have been implicated in familial (hereditary) CJD including GSS (Gerstmann-Straussler-Scheinker Syndrome) and FFI (Fatal Familial Insomnia) which together account for about 10% of cases. Under these circumstances the odds are tipped in favour of PrPsc conversion and so the disease tends to manifest at a younger age.

These syndromes are of course entirely separate and distinct from prion diseases initiated by the exogenous administration of PrPsc, as in human BSE.

Chris

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« Last Edit: 06/10/2004 10:30:31 by chris »
 

Offline TomG1987

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #65 on: 04/10/2004 19:49:52 »
Ah, but how strange that the process of evolution didn't remove those who's genes would give a greater chance of contracting such a prion disease. It seems that there must be somewhere along the line of time a mutagen that causes these genes to keep entering the gene pool. And interesting about as we begin to live longer, I think that's almost certainly going to happen any thoughts on treating these diseases using anything but SUPLHATEY THING so that synaptic pathways that are lost can be rebuilt, and partial memory at least restored (in such diseases as Alzheimers), perhaps a chemical that could make the PrPc form more stable, so that the degenerative effects of the diseases can be slowed, or with enough treatment halted? And to answer the reply above, I believe the Protein only theory is now widely accepted, even if it is a frightening thought that such harmless molecules at proteins could cause such devastating effects. I'm particularly interested in neural degenerative effects of alzheimers (hope im spelling this right, im only 17 after all!) and onset of dementia, as I lost my grandmother to the disease. Any thoughts, links or anything please post them, I'm a thirsty for more :P

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Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #66 on: 05/10/2004 16:07:26 »
For genes (such as those that increase the chances of developing a prion disease) to be lost from the gene pool there must be some form of selective pressure to drive their removal. One way in which this can happen is if the disease renders individuals sterile, or kills them before they have a chance to reproduce, thus preventing them from transmitting the trait to subsequent generations. An example of a disease which behaves like this is cystic fibrosis.

But if the disease doesn't kick in until after the age at which people reproduce, then the selective pressure is considerably weakened and the disease is more difficult to eliminate from the population. This is the case with diseases like CJD and Alzheimer's.

Another consideration is the existence of a so-called 'balanced polymorphism'. This occurs when a harmful condition actually provides an affected individual with an advantage under certain circumstances. Sickle cell anaemia, which is very common in Africa, whilst debilitating for sufferers protects carriers from malaria. In this way the gene is artificially preserved at a high frequency in the population.

And then there's the new mutation rate. With every generation individuals acquire new mutations; in fact 10%, maybe 20%, of new cases of haemophilia in the UK may represent new mutations. So it's perfectly feasible for new mutations to sustain the disease rate too...

There's no easy answer. But on this week's radio show we'll be discussing how to repair the diseased, injured or damaged brain - see http://www.thenakedscientists.com/html/next_week.htm - for details.

Best

Chris

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Offline TomG1987

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #67 on: 12/10/2004 21:11:24 »
I just bought the book
'Prion Biology and Disease' By Prusiner (spelling?)
Cracking book, but i dont somehow think my target of finishing it before december is obtainable :( Good radio show this week by the way

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Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #68 on: 14/10/2004 13:13:56 »
I'm glad you enjoyed the show this week. It was a timely topic given the subsequent furore over Christopher Reeve.

I've not read Prusiner's book, but I'd like to. I am currently looking into doing another show on Prion diseases, so watch this space !

Where are you based then Tom ?

Chris

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Offline Moka

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #69 on: 29/10/2004 13:22:44 »
quote:
Originally posted by chris
the structure of PrP is well established and the switch to a pathological (scrapie) form involves a conformational change from a predominantly globular to a beta-pleated sheet architecture.

As such, this fibrous beta-pleated sheet structure is extremely stable and resilient to most degradative mechanisms. It is for this reason that contaminated neurosurgical instruments proved so difficult to disinfect and are now routinely destroyed after a procedure.



Hi Chris;)

Sorry for the misunderstanding... I meant exact structure determination. Since then I've found some papers alluding to the fact that there's no exact structure yet. Low-resolution electron crystallography studies were published. X-ray and NMR have troubles with insolubility (? correct it please, if I'm wrong).

Yesterday I've heard a very interesting lecture about ubiquitin-dependent protein degradation. How useful could it be, labelling the PrPSc with a couple of ubiquitins and... goodbye:) Eeehhh... I'm dreaming...:)

Bye,
Moka
 

Offline chris

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #70 on: 30/10/2004 11:44:28 »
Nice thoery but the problem is that the PrPSC aggregates are very resistant to degradation so you could label them with anything you liked and they still wouldn't break down. The stuff can remain infectious on surgical instruments that have been autoclaved !

I'll have to look into the structural work as I'm a year or so behind on that data. Sorry.

Chris

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Offline TomG1987

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #71 on: 09/11/2004 15:51:27 »
Well Chris, I'm not based (in the sense of researching) anywhere at the moment, i am only 17 and about to go for interviews to study veterinary medicine. But Prions have interested me for a while, so i decided to try and find some good sources of information on them, and with the exception of a few research dissertations I have obtained from students I know and Pruisner's book, this forum has been the only other good source of up to date knowledge. Sorry if you thought i was a research bod :S

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Offline Simon

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #72 on: 09/11/2004 17:58:38 »
Hi guys, if you are interested in the structure of prion deposits check out some of the work done on Amyloid fibres made from transthyretin (TTR) and kappa light chains. Essentially amyloid (including the aggregated prion protein) consists of beta structure formed perpendicular to the fibre axis, and held together by fairly well ordered hydrogen bonds. Interestingly such fibres can be formed from all proteins by simply heating and/or dropping the pH leading to suggestions that amyloid represents the "primordial" protein fold (I think Chris Dobson from Cambridge university is the main bod within this field). As such all amyloid diseases represent diseases of protein misfolding, and normally occur in later life due to protein ageing and/or breakdown in cellular scavenging systems.

 The structure does vary quite a bit between different proteins based on sequence, however all fibres share a common cross-beta fold with substantial amounts of disordered peptide surrounding this core structure. There are also various other co-factors involved, one of which being a protein called serum amyloid P component, which effectively hides the amyloid from the normal scavenging systems. Much amyloid/prion research is based on therapies to try and disrupt these sorts of co-factors.

Amyloid diseases include Type II diabetes, Alzheimers, vCJD, rheumatoid arthritis and the systemic amyloidoses.

 If anyone is interested further I recently wrote a review that I could email newbielink:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15011948 [nonactive].

Simon
« Last Edit: 09/11/2004 18:02:35 by Simon »
 

Offline tweener

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #73 on: 09/11/2004 18:15:14 »
This thread sounds soooo interesting.  I wish I understood even part of it!

----
John - The Eternal Pessimist.
 

Offline shicky42

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #74 on: 22/11/2004 16:17:15 »
quote:
Originally posted by bezoar

And so, what's the rest of the story?  Did he receive monoclonal antibodies, and if so, was he cured or was the disease held in check?

Bezoar



I very curious, was there a cure?  My husband may have to get this biopsy.  Have there been any successful cure?
 

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Re: How are infectious prion diseases, like BSE, transmitted?
« Reply #74 on: 22/11/2004 16:17:15 »

 

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