Naked Science Forum
Life Sciences => Cells, Microbes & Viruses => Topic started by: genegenie on 24/08/2003 13:23:48
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I understand that prion diseases such as Creutzfeldt-Jakob disease can be inherited (due to a mutation in the PrP gene), or acquired by transmission. Does anyone know the proposed mechanism involved in infectious prion diseases ie. how does this variant protein (that contains no genetic material) alter the conformation of endogenous Prp proteins?
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The current theory is that the rogue prion induces a conformational change from an alpha-helical, globular structure to the fibrous beta-pleated architecture characteristic of PrPsc. How it does this is not known. It's a fascinating area...
TNS
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So the, why does it take so long for the symptoms of the disease to manifest?
Bezoar
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Apparently it takes a while for the variant proteins to accumulate and cause symptoms. It's amazing, and quite frightening!
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A while? Twenty years or so? It is amazing and frightening. I was wondering if the body didn't mount some kind of defense and then finally succumb. For something that takes that long, you'd think over a twenty year period, medical science could find some way to interrupt the process.
Bezoar
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Well, there are multiple ways to interrupt the process, including antibodies, but they are only any use if given before the person becomes symptomatic. Since the disease follows an accelerating course once neurological symptoms appear, initiating treatment at that stage is a bit like slamming the door once the horse has bolted.
The disease takes a along while to manifest because initially there are very few infections prion particles to initiate the conformational change. However, as more prion proteins are converted to the pathological form the abundance of abnormal prion grows exponentially since, in essence, it catalyses its own production.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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So then, is there an antibody to Mad Cow Disease, or I think you all call it BSE? And if so, why not immunize everyone with any possible exposure? Is there any test to detect it before it becomes symptomatic?
Bezoar
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I wasn't aware that there is treatment available....I'm keen to hear more about that. As far as I know, diagnosis can only be confirmed by autopsy. Build-up of these variant proteins cause plaques that damage the brain.
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A novel feature of human BSE is the accumulation (presumably by amplification) of the abnormal prion in peripheral lymphoid tissue PRIOR to the onset of clinical neurological symptoms.
A man from the southwest of the country, by sheer serendipity, underwent appendicectomy a couple of years before being diagnosed with variant CJD (human BSE). Subsequent re-examination of the appendix specimen (which for some reason had been kept, I can't remember why) revealed the hallmark deposits of vCJD. This led to tonsilar biopsy being used in suspected cases.
The only way to diagnose the condition with certainty, during life, is by brain biopsy.
In terms of interventions, researchers have found that blocking certain parts of the immune system (with monoclonal antibodies) can stop prion transmission and amplification, but as I said before, only before it has become clinically manifest.
Chris
This had led to tonsillar biopsy
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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
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You'll be happy to know that a researcher at the National Institute of Health has come up with a way of treating prion-infected meats to eliminate the infectivity of said prions. I stumbled across his work in the course of a paper I was writing on the horrible things that are happening to our food supply. This made me feel a bit better...check it out.
http://www.nih.gov/news/pr/may2003/ninds-05.htm
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In the above-mentioned (and linked) paper it says
"The scientists found that they were able to retain the basic texture and flavor of the processed meat while reducing the prions to non-infective levels. This may have application in improving the safety of meat products."
...so who tasted the (prion-contaminated)meat before and after treatment to conclude that the processed meat retained "the basic texture and flavor" ???! [xx(]
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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From the sound of what they were testing on (hot dogs), I don't think there would be much flavor or texture worth retaining.
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No words of wisdom here.
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Agreed.
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They probably fed it to cows.
In seriousness, they probably tasted the meat before adding the prions, then afterwards checked for prions before tasting it again.
Besides, the proteins in processed meats are pretty much denatured already from the processing, so it's not like pressure and heat are going to make it any worse.
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The point is that prions are clearly not denatured by the kind of processing that is used to prepare 'convenience foods', hence the 120+ cases of human BSE. Prions have been found to be resistant to autoclaving. Indeed contaminated surgical instruments, used previously on individuals who were later found to have been incubating CJD at the time of their brain surgery, have been implicated in the transmission of the disease to other patients.
Furthermore, not long ago a report found that in Germany brain-derived material was still finding its way into German sausages and indeed a friend of mine cut a thin section through such a sausage and stained it with a subtstance that highlights the presence of brain tissue. The test was positive. A paper also appeared in one of the medical journals based on the same test that predicted some types of sausage contained upwards of 15% brain tissue. Germany defended the use of this material by citing the low frequency of BSE in their country. But what they couldn't explain was the huge disparity between the number of cases of BSE you would expect to find in Germany - based upon the number of cows imported from the UK where the frequency of BSE was well established - and the number of cases of BSE that Germany actually reported. Perhaps we can cure BSE... just by shipping cows to Germany ???
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Chris, so if Prions are resistant to autoclaving, how can surgical instruments be sterilized for protection? Would submerging them in alcohol work?
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No. The only way to prevent infection is to throw away the kit.
This has led to the production of single use instruments for certain surgeries and in high risk individuals.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Good God! Does nothing kill these prions? What about freezing or burning? Or nukes? Or bleach? If not, can these things be used in any way constructive, as in an antidote?
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So Chris, do you eat beef?
Bezoar
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Of course. BSE wasn't just in beef. Contamination made it into many household items incuding cosmetics, jelly (what Americans call jello for some reason, probably because they call jam jelly, god knows why), event capsule casings and boot polish (not that many people eat that).
It's also probable that there are some sheep around that are carrying BSE, but because it is indistinguishable from scrapie (in a sheep) which is not perceived to pose a threat to humans, it will be very difficult to track down.
The beef here in the UK is now the safest in the world. I'm not being defensive, merely honest. The safeguards in place here now are very strict. I would much rather eat bef here than in other countries, like Germany and France that denied they had a problem (yet we have statistical and biological evidence that they did) where the safeguards are far fewer. Also worth bearing in mind is that the practices used in the US to rear beef involve exposure to huge doses of hormones and antibiotics. These agents can be transmitted to people consuming dairy and beef products with who knows what impact upon your health.
It always amazes me that Americans are so paranoid about BSE given that there ahve been only about 120 human cases from a total exposed population of millions (most likley the whole beef eating population since the (cow) BSE incidence was exceeding hundres of thousands of cases annually at its peak).
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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"Good God! Does nothing kill these prions?"
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No words of wisdom here.
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OOPS! I hit the wrong button.
I was going to add to the previous post: Are prions alive? Can they be killed or is the better word "denatured" as you've used, Chris?
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No words of wisdom here.
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Read the article I linked to. Prions can be denatured. I emailed the researcher that developed the process...they're already working on perfecting it for industry use. They're already lobbying to get FDA regulations mandating the procedure when it is complete.
Personally, I'd rather just see them disallow the use of any animal's brain tissue. Certain things just shouldn't be eaten...brains and genitals for instance.
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I've read the article you linked us to cannabinoid, and they don't actually mention denaturing, they use the term 'inactivation'. They also say 'processes such as autoclaving and exposure to strong alkali or bleach are known to kill prions' which as far as I am aware, and Chris has verified, is actually incorrect (just an observation).
My concern about this reported inactivation, is that due to the nature of prions, can they re-activate when conditions are normalised?
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I read the article, but it really only applies to highly processed foods that can't really be hurt by drastic pressure and heat. I don't think a steak would survive in recognizable form. Maybe the process could be adapted though.
Personally, I think brains are very good when they are cooked right. I've never been much on the other end of the animal. [:p]
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No words of wisdom here.
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Prion is a termed coined by nobel prize winner Stanley Prusiner and stands for "proteinaceous infective particle" (they switched a couple of lettes around to make it sound better !)
Like enzymes, prions are proteins; they are not alive and cannot be 'killed'. But they can be 'denatured' which means affecting the function of the protein by altering its structure. So when a steak goes in the pan it changes colour, consistency and taste because the proteins it contains permanently change their shape (conformation) in response to the heat of the cooking process.
In the brain the normal prion protein - PrPc - is a globular shape. We don't yet know what it does. But the prion protein can also exist in the form of a flattened fibrous sheet. This is the pathological prion found in scrapie, CJD and BSE. It's referred to as PrPsc and it is very stable and heavily resistant to breakdown enzymically, chemically or with heat and other denaturing agents. It is a problem because this abnormally shaped PrPsc prion protein can, rather like a religious fanatic, go around inflicting itself on normal prions and forcing them to change to the abnormal form too. So in this way, the conversion of the brain's healthy Prpc to PrPsc follows a positive feedback loop because you make more abnormal prions that can then co off an convert more normal prions to the abnormal form. The proces therefore accelerates exponentially. The accumulation of the fibrous prion proteins in the brain produces pathological effects including neuronal cell death and the ensuing dementia.
The evidence for this mechanism is that high levels of the abnormally folded prion protein are found in the brain at death. Mice that have been genetically engineered to lack the normal prion protein can't get the disease. And people who have had brain surgery and been operated on using the same instruments (autoclaved) as someone who has subsequently developed CJD, themselves have gone on to develop CJD.
An interesting, though rare, disease. Your chance of getting it is less than being hit by lightning. The sporadic disease (CJD) crops up with a frequency of about 1 person in a million per year. Hence there are about 60 cases a year in the UK. BSE is much more difficult to predict because all of the victims so far have all shared a gene in common, suggesting that there might be an inherited susceptibility to the disease. Since that gene type is carried by about 20% of the population the future is difficult to predict, although the anticipated number of human cases of BSE has now been hugely down-graded from the terrifying suggestion of "millions" a few years ago to "hundreds" now.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Thanks Chris - That is the best description of prions and the various diseases they cause I've yet to hear.
John
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It would seem that if the abnormal prions can go about coercing the normal ones to go abnormal, then there should be a way to reverse the process, with the normal ones coercing the abnormal ones to go normal. Theoretically, there should be a cure, and maybe it should focus on the resistance and reactivity of the normal prions.
And Chris, do you eat beef?
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Bezoar - I did reply to your beef enquiry - see above ! Maybe you've got BSE and forgot [;)]
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Great idea bezoar! Perhaps when they figure out how the variant protein alters the normal protein, that could be possible. I suppose I just don't like the idea of inactivation by denaturation, because I think about how easily renaturation occurs in heat denatured DNA. But of course, I'm speaking out of total ignorance [8D]....just my thoughts.[?]
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There is a trial on-going with an agent derived from beech chippings called pentosan polysulphate which is administered intraparenchymally - i.e. directly into the brain. In the one case for which there is robust evidence at the moment it seems to have halted the progression of the disease, and produced some modest functional improvements. The agent is believed to hinder the interaction between the abnormal prion and its healthy counterpart.
However it is worth bearing in mind that most of the symptoms of the condition are due to neuronal cell death and so treatment isn't merely a case of removing the pathological deposits.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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But isn't the neuronal cell death triggered by the abnormal prion?
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Yes, that's what we believe. But my point is that the disease only becomes clinically manifest, and robustly diagnosable, once there has been (considerable) neuronal cell death. To reverse the effects of the clinical syndrome you would need to not only prevent the further accumulation of pathological prions, but also replace the lost cells.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Is it possible to replace the lost neuronal cells? If so, how would the new cells be "trained" back into the neural network? I guess what I'm asking is wouldn't the person's memories and skills be lost?
John
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That's essentially what people are trying to achieve with stem cell therapy, and neuronal cell grafts taken from foetal tissue. It has shown some promise in patients with Parkinson's Disease, and a trial is underway on Huntington's too.
The reality is that we have no way of knowing how well the new cells integrate into the existing neural network and we have to go on clinical observations only, which could be confounded by a host of factors.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Isn't kuru also a prion disease?
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Tweener:
Since prions exist in and infect brain matter, your chances of getting one from a steak are pretty slim, even from an infected cow. Processed meats are where the danger lies. And since processed meats can be treated (or will be able to be treated in the near future) I wouldn't worry too much about it.
In the meantime, if you're really worried about it, avoid processed meats, ground beef (unless you pick out the cut of meat and have them grind it right in front of you), and all types of sausages.
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quote:
Originally posted by bezoar
Isn't kuru also a prion disease?
Yes, it was prevalent among the Fore people of New Guinea who practised ritualistic cannibalism which involved eating the brains of dead relatives. Since it was mainly the women that carried out the ritual, the disease predominated amongst the females of the tribe. It disappeared once the practise ceased, indicating the capacity of infectious prions to be transmitted via the oral route.
Kuru actually means "he who trembles" and is a reference to the symptoms experienced by sufferers as the disease becomes manifest and they develop involuntary movements. In some cases these involuntary movements were sufficient to throw some people into their camp fires, though whether they did this partially voluntarily in an attempt to escape the symptoms tey were experiencing, no one knows.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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That is an interesting story. You guys never cease to amaze me. That's a good story just in time for Halloween.
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Oh, I thought you meant the rest of the tribe threw them into the fire. Thought they were just preparing the next meal. I didn't think the symptoms were painful at all. My impression was that it was just a gradual neuro degeneration.
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It causes mental anguish owing to the psychiatric changes experienced by some - uncertainty and stress caused by the symptoms. BSE sufferers frequently do complain of pain because the normal systems that relay pain stimuli to the brain and control our perception and conscious experience of pain are disturbed by the disease process.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Topic of "Prions" and "BSE" from October, 2003 talking about other types of contamination that perhaps have occurred or are known to have occurred. My physician had recommended melatonin, but cautioned me to be sure that it was synthetic and not produced from 'cow'. It proved to be a study in 'who knows'. In searching it out I found that most folks having this product on their shelves knew very little about it. Most assured that they stocked nothing but synthetic and this subsequently proved to be true in most cases. Interesting subject matter in this article. The pursuit of how prions function is facinating and we are hearing a lot about the scientists' interest in them these days.
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Why doesn't our body break down the BSE? Why are Prions processed by oral ingestion and not destroyed by our enzymes? I need answers, I am a college student and this is for extra credit can someome please help, thanks.
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You can't uncook a steak. The intermolecular forces that fold proteins together are not quite the same in frequency and structure that bind DNA.
Do they have any idea at all how prions do what they do? Is it a genetic change where RNA is creating proteins incorrectly, or do they alter existing proteins?
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They alter existing proteins apparently. There's an intersting article at http://www.cyber-dyne.com/~tom/prionSP.html which also talks about genetic susceptibility to prion disease. Nasty stuff!!
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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.
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The point is Jules, that since the abnormal form of the prion protein seems to be heavily resistant to digestion with proteases, it is hard to envisage how an antigen presenting cell could chew it up and present it effectively in the first place, in order to initiate an immune response. This may be why there is so little immune response to the accumulating pathological prions.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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.
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The point is Jules, that since the abnormal form of the prion protein seems to be heavily resistant to digestion with proteases, it is hard to envisage how an antigen presenting cell could chew it up and present it effectively in the first place, in order to initiate an immune response. This may be why there is so little immune response to the accumulating pathological prions.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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.
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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.
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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.
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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?
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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".
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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...
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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.
'To know when to stop, is to know when you're beaten. Never stop, and you're never beaten'
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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!
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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.
'To know when to stop, is to know when you're beaten. Never stop, and you're never beaten'
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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
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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
'To know when to stop, is to know when you're beaten. Never stop, and you're never beaten'
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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
'To know when to stop, is to know when you're beaten. Never stop, and you're never beaten'
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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
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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
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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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
'To know when to stop, is to know when you're beaten. Never stop, and you're never beaten'
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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 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15011948.
Simon
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This thread sounds soooo interesting. I wish I understood even part of it!
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John - The Eternal Pessimist.
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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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Drinking alcohol and beer while being diagnose with prion disease, how effective could that be? Could a person with prion disease continue to have a beer occassionaly?
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Please tell us a bit more about your husband and his condition, including how long he has had symptoms and how it was first picked up / diagnosed.
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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*Thinks Prions have made his brain fry* (not in a clinical or even literal sense)
thanks to this thread and good ol prusiner ive gained 2 offers out of 3 choices on UCAs for veterinary medicine intercalated with biochemistry :D
BUt all is not finished for me and prions, for i am still so intrigued by them, any new evidence come to light about reasons for ranbdom flippage of PrPc? or any new treatments (apart from thew on mentioned at the start of this thread which as i undertsand it halts the diseases). and lastly, diabetes a prion disease? if i read the members post a few back? type 2 albeit but how can that be? i thought diabetes was inability to control insulin, and so inability to control glucose and glycogen, i never knew it could be even vaguely related to prion pathogenisis
[?]
'To know when to stop, is to know when you're beaten. Never stop, and you're never beaten'
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Congratulations on your offers - where are they from ?
Chris
"I never forget a face, but in your case I'll make an exception"
- Groucho Marx
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Well Cambridge rejected me unfortunately, (which was strange as one of the interviewers in the veterinary interview said 'Excellent' when i gave him an answer about prions, cant remember what though, but the college interview didnt go so well i dont think) however the Royal Veterinary College in London have offerd me a place, as have Bristol Veterinary School. I only applied to three so not a bad result considering nobody in my school has had an offer first time from any vet school for over 5 years. I don't know which one to go to though, but if I go to London I can do a research elective into prions, which could be fun. Then again Bristol have invited me to apply for avacational scholarship to research immunology and virology :S Don't know which to go for.
'To know when to stop, is to know when you're beaten. Never stop, and you're never beaten'
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quote:
Originally posted by chris
...jelly (what Americans call jello for some reason, probably because they call jam jelly, god knows why)...
"Jello" is a brand name of a food product that is called "gelatin" generically.
Much like you folks calling a vacuum cleaner a "Hoover" as if there weren't a thousand other folks making them.
Jelly (shorthand for "gelatin", jam, and preserves are used to differentiate between (respectively) gelatinated fruit juice, gelatinated mostly-macerated fruit and more-or-less whole fruit preserved in gelatinated sugar-sauce.
When the British learn how to spell Aluminum, then you can whine about odd names for American stuff. 'Till then, I wouldn't poke too much fun at what Yanks call things. The land of "Spotted Dick" and Welsh street names with 47 consonants and two vowels probably doesn't have much room to be having off anyone else's language idiosyncracies.
Thanks,
L. Lisov
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While I have not read all contributions to this topic, it seems to me that we are still treating mad cow disease and BSE as a food related topic. I recently had occasion to search the string, "What drugs contain bovine material" at AskJeeves (http://ask.com) and got 16,800 hits. After reading some of the references I concluded that the BSE/Mad Cow Disease issue for completness must include the issue of bovine sourced drugs.
phdkso