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Prions – Infectious Proteins With no Nucleic Acids

by Vincent Racaniello, PhD
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    00:01 Hello and welcome to Prions. We are going to be diving a little deeper into this topic.

    00:07 And after you've listened to this video, I hope you'll understand two assays for detecting prions. You'll know why Mad Cow Disease and Chronic Wasting Disease may be a threat to the food chain for humans. You’ll comprehend the species barrier to prion infections, and you'll be able to trace the possible origin of prion diseases.

    00:36 Prions cause diseases that we call transmissible spongiform encephalopathies, which I'll now refer to as TSEs, and here are some of the human TSEs: Creutzfeldt-Jacob disease (CJD), Fatal Familial Insomnia (FFI), Gerstmann Straussler syndrome (GSS), Kuru, and variant CJD (vCJD).

    01:02 These are human TSEs, they are also TSEs of animals.

    01:07 TSEs or prion diseases are protein misfolding diseases. They involve the misfolding of a normal cell protein. So let's explore exactly what that means. The normal cell protein involved in TSEs is called the prion protein PrP with the superscript C, which means it's the cellular version. And shown here on the left is the structure of the PrPc protein. It's the normal version. You can see lots of swirls in this protein, those are alpha helices. This protein has high alpha helical content and very low beta sheet content. The pathogenic version of PRP, which is associated with TSEs as shown on the right, is called PrPsc, SC stands for scrapie, because that was the first TSE discovered, and the one where the role of the prion protein was figured it out. This protein is abnormally folded. Now we don't have the structure of this solved, but we think it has a lot of beta sheets and you can see those four long sheets going up and down in green and in yellow, those are beta sheets. So this is a conformational alteration of the normal protein. We have the normal protein and a conformationally altered PrPsc, and that PrPsc is pathogenic, when you accumulate that in your brain, you develop a TSE. It’s a very unusual disease. So pathogenic prion, PrPsc, is a conformational isoform of a normal host protein PrPc. Prion, the word prion stands for proteinaceous infectious particle, and you might hear me say “prion” or “prion”. I really don't know what's right, when you have a word invented by people, what's the difference on how you pronounce it? As long as you say “prion” or “prion”.

    03:14 Prions are normal proteins on the outer surface of neurons. They are found in a few other places, but mainly on the outer surface of neurons. As in this slide, you can see at the bottom, a lovely neuron with the cell body, and then the axons and dendrites, and there on the surface is the normal cell, prion protein PrPc. So it has functions on the outside of a neuron, it is GPI linked. So it is not a transmembrane protein, but it is linked by a chemical linkage. When you acquire the pathogenic form of prion, PrPsc, let's say you ingest some meat that has bovine prions in it, bovine pathogenic prions. You'll eat that beef, it will go into your intestines, and shown here on this side, is a layer of mucosal cells, and on one of those mucosal cells, there are some normal PrPc, and you should be able to tell me which one it is, because you know it doesn't have a lot of beta sheets, alright. And then coming in just to the left of it, is a little bit of the abnormal protein PrPsc. It has beta sheets. You've just eaten this, so that's coming into your intestines. What we think happens, it comes in and causes the normal protein to convert to the abnormal form. It causes it to convert. This is really incredible.

    04:39 The abnormal protein finds a normal version of the protein and it makes it fold, like it is folded, from PrPc into PrPsc. So that’s shown here, the pathogenic protein is next to the normal protein, and then the normal protein is now converted into a pathogenic one. It now has a lot of beta sheet structure. You can see those two proteins are now PrPsc.

    05:02 And the idea is, this happens in the intestine, you then ingest, you then take up those proteins and they travel via various pathways, to neurons in your central nervous system and there they convert additional PrPc to PrPsc and when you have enough or more PrPsc, then you start to develop the symptoms of a TSE. And eventually you die, you will always die when you start to develop a TSE. We don’t yet have any way to stop it. Fortunately these are very rare.

    05:37 So there are three ways that you can acquire or develop a TSE, also known as a spongiform encephalopathy, because of the spongy appearance of the brain when it accumulates a lot of these PrPsc proteins. So again on the left we have our normal protein PrPc, on the right, the abnormal PrPsc. There are three ways to get from normal to abnormal. You can acquire some PrPsc, you can eat it in beef or it can be introduced into you by a corneal transplant, if you get a cornea from someone who has PrPsc, maybe they don't know about it at the time when they die and donate the cornea, you can acquire PrPsc. You can get it from human hormones or other blood products. There are ways to get it. So this is the infectious form. You get that PrPsc and it converts your PrPc into more PrPsc and you develop the disease.

    06:36 A second way you can acquire this is by genetics. The luck of the draw. You get a mutation from your parents in the prpn gene, the gene encoding PrPc. Single amino acid changes enough to, at some point in your life make PrPc, start to misfold, and once there's one PrPsc somewhere in you, it then makes all your others misfold. So it’s a genetic disease. So far we’ve got an infectious disease, we have a genetic disease, and finally there is what's called a spontaneous disease, where you don't eat any contaminated beef, you don't get a corneal transplant, you don't have a genetic mutation that predisposes you to misfolding, but for some reason at some point, one day some of your PrPc misfolds and becomes PrPsc and you go on to develop a TSE. Alright, three ways that you can get this, in the end they are all fatal.

    07:32 They all can be transmitted.

    07:35 So here is a graph showing you the number of cases of Creutzfeldt-Jakob disease deaths in the United States from like 1979 to 2011. You have deaths in the bars and the death rate is in green. So what you can see is that the rate is low, it's 150 to 200, and now maybe 400 per million population. It's rare but not unheard of, people die of this regularly.

    08:05 And the incidence, this is Creutzfeldt-Jakob, a certain kind of human TSE, incidence is slowly rising with time. We don’t know why this is the case, but it's puzzling and the more people with Creutzfeldt-Jakob, the more people are likely to get it, because they can transmit it to them. So this is a combination of mostly sporadic or spontaneous TSEs and genetic. Mostly spontaneous, very, very little from eating contaminated material.

    08:36 Nevertheless it's a substantial burden and it causes a 100% fatality, you never can recover from this. Hopefully one day we’ll have drugs or some way of reversing it, but we don't at the moment.

    08:49 When you acquire a misfolded protein, the agent first accumulates in the lymphoreticular and secretory organs, and eventually spreads to the central nervous system. And in the central nervous system, the pathology includes death of astrocytes, astrocytosis, vacuolization, the holes in the central nervous system, the brain that makes it be called spongiform TSE, that's the 'S' in TSE. And you eventually lose neurons, slowly but surely neurons go, and you lose many of your functions. You have cerebellar ataxia. What does that mean? You can't walk, you have more and more trouble walking, until at one point you can no longer walk. You tend to have dementia, you go crazy, you don’t recognize people, you start to just stare and you stop talking, akinetic mutism, you simply stare straight ahead without saying a word. There are other issues too, you can have psychological problems, you can yell and scream at people for no reason, depends on which TSE you are getting. And then in any time from months to years, it can be a year or it can be 20 years of incubation, you die. As I said, these are uniformly fatal, no way to prevent the death. So pretty scary and a bit insidious. They come from nowhere. There's no inflammatory antibody or cellular response to this protein. It's a normal cell protein. It's just misfolded and our immune system does not recognize it as different, so you don't make any antibody response, so there is no way that you yourself can prevent this disease from happening. Only if we can somehow give you some drugs one day, which we don't yet have.

    10:30 Alright, I’m going to tell you about one test for TSEs that was developed a long time ago, which for many years was the only way you can tell postmortem, whether someone had a TSE. And I said postmortem because you need a little brain tissue in order to do this, and when someone presents their doctor with early symptoms of a TSE, there are in no shape to have a brain biopsy, so this is done after they die. The observation was that PrPc, the normal protein, we see it in its structure on the right, on the left is a stretched out version of the protein. If you take say a brain extract from someone who died of a TSE and you digest it with an enzyme that digests proteins called proteinase K. That enzyme will completely digest this protein away into bits, and if you run a western blot, which is a way to detect PrPc specifically with an antibody, you won’t see anything because it's digested away. If you take the PrPsc version, which now has lots of beta sheets and you do the same thing, you digest it with proteinase K, that is largely resistant to digestion.

    11:41 You clip off a little bit at the left end of the protein, the end terminus, but pretty much the protein is resistant to proteinase K digestion. So right away this is a nice way to distinguish the normal protein from the pathogenic protein. And you could take a sample from a person and subject it to this assay. If all the PrP is digested, they don’t have a TSE, but if it's resistant, they do have a TSE. And you may ask, what does it matter after they die? Well you want to know what people died of, and you want to make sure they're not going to contaminate someone else. So for example very recently, someone showed up at an emergency room, they had shot themself in the head, an attempted suicide, and only after few hours did they find out that this person had a TSE, he was going to die, so they decided to take their life, but in the meantime he contaminated all the emergency room with brain material and if they didn't realize he had a TSE, which they figured out by a diagnostic test, lots of other people could've acquired it as well.

    12:43 So let’s talk a little bit about the gene itself encoding this PrPc protein.

    12:47 Remember I said it is a normal cell protein in you, it is encoded by a gene, like all proteins are.

    12:54 The gene is called prnp, so PrPc is encoded by the prnp gene, it has a normal cellular function. In animals we can give animals, experimentally in the laboratory, these TSEs, by inoculating them with homogenates of brains from people who have died of the disease.

    13:17 We don’t usually do this with people, we will take a sheep with scrapie, or a cow with BSE. We will grind up their brains, we inoculate it into an animal like a mouse or hamster, sometimes we can transmit the disease to another species. So this is the basis for what I’m going to tell you for the next few slides.

    13:35 If you take a mouse, and let’s say you have a mouse that developed the TSE for whatever reason. You grind up its brain, you inject it into another mouse, that mouse will develop a TSE. However, if you delete the prnp gene from that recipient mouse, and we can do this genetically relatively easily, you can make a knockout mouse recall for both copies of the gene, remember we have two copies of most of our genes, that mouse now will not develop a TSE when you inject PrPsc right into its brain. So the prnp gene is essential to develop a TSE. Think about it, it makes sense, if you don't have any PrPc protein in you, there's no way that a little bit of PrPsc that you acquire can cause disease, because it doesn’t have any PrPc to convert to the pathogenic protein. Now we can’t delete genes in people, otherwise that would be one way of preventing TSEs. But it could be that in us, we need this prnp genes. So it is probably not a good strategy. Alright, so now you need to remember prnp is essential for a TSE.

    14:43 Let’s now turn to two diseases of animals that are apparently a threat to our human food supply. The first is called bovine spongiform encephalopathy or mad cow disease. I’m sure you've heard of it. This was a disease that appeared in the 80s in the UK, and we talked about this in our introductory prion lecture. You can go back there and check that out.

    15:11 What happened in the UK was they feed cows meat, protein to make them grow quickly, so they can slaughter them and sell it, instead of giving them corn or grass which takes longer.

    15:23 Not a lot of grass and corn areas for cows to graze in the UK, so they feed them meat.

    15:28 Where does the meat come from? They take other animals and they grind it up, feed it to cows.

    15:32 Those animals include other cows who die, sheep, and it turns out that some of those animals have TSEs and we don't know it, because they're dying and we are not diagnosing why.

    15:43 And in the early 80s, they changed the way this meat was prepared. And apparently that allowed scrapie prions to get into the cow food supply, and that caused this outbreak of bovine spongiform encephalopathy. So it's basically a form of cannibalism, we are feeding cows themselves, as well as sheep, with a TSE and the cows developed TSEs. So it was a big outbreak of TSE in the UK, bovine spongiform encephalopathy rather, among British cattle.

    16:14 Hundreds of thousands of cows were slaughtered to get rid of it and many millions in fact acquired the infection. The problem was, this didn't go detected until some of that beef got into the human food supply. As you know we eat cows, some of us do, in the form of steaks and hamburgers, and even if you have a well-done meat, you know if you listen to a parasite lecture and you know you have to cook your meat well. Well it doesn’t do anything if there's a prion in it because prions cannot be inactivated by cooking. In fact they can’t be inactivated by a lot of things, which is another reason why they are very scary. So here is a graph of the outbreak of BSE in cows, those are the orange colored bars, and you can see the number of cases, which is listed on the left, goes up starting after 1987, peaks in about 92, starts to go down again. So at some point we said: “Uh oh, we are making these cows get BSE, let's change the feed preparation”, they changed it, they got rid of prions, you can see gradually the number of cases in cows go down. We thought we had this solved, then all of a sudden in 1994, we start seeing a new kind of Creutzfeldt-Jakob disease in people, those are the green bars going up and then going back down again. It's a new disease, because it has a different incubation time, it is much shorter than classical Creutzfeldt-Jakob. It happens in younger people, and they die much quicker, and the epidemiology said this is because of BSE, and there was a peak and then finally it went down because we stopped feeding cows scrapie prions and eventually we got those out of the food supply and so the human cases declined. There is a big lag because there is a long incubation period here. So a variant Creutzfeldt-Jakob arose because of feeding cows scrapie proteins and then they in turn transmitted it to humans.

    18:08 So that's a big problem of course, and we’re still worried about it.

    18:12 In cows, new cases of BSE still occur, very rare, but they occur. They are probably sporadic, we no longer feed cows scrapie prions as far as we know, so a cow now and then, it is extremely rare, but now and then will develop a prion disease, and it is probably the sporadic form where the PrPc simply misfolds and you get disease. The problem with cows is that, we slaughter them pretty early on in life, about two years or so, and usually they don't develop the disease until five years, so they may be incubating prions but we don't know it.

    18:49 So that's why it's a problem. Now we would like to protect our food supply from bovine prions, The problem is of all the cattle we slaughter worldwide, in the US and Canada, we have a lot of statistics here in Europe, less than 2% are actually tested. We don't look at the meat in any way that would reveal if there were any problems with those animals, and in fact you have to look at the brain tissue to really know. And obviously it would be good to have a diagnostic test to do this. The Western blot test that I showed you before is really too laborious to look at every cow that’s slaughtered in the world, this is simply not going to work. It's going to put the price of beef through the ceiling, which may not be a bad idea in the end. I do like meat myself but maybe it's not a good practice.

    19:37 So here is a graph which shows you how rare BSE is in cattle since 1993 or so towards the end of the BSE outbreak in cattle. And these are colored according to where the cows were, when they were diagnosed with BSE, so you see they are not too many. Each of the little blocks whether it's yellow or blue or light blue, is just one case. So you can see in the US, which is orange, there is just a handful of cases, 1, 2, 3, 4 cases on this graph. One of them was imported from Canada and another one was born after the feed was changed, so that's probably a spontaneous case. Canada is listed in blue of different colors depending on when it's before or after the feed ban. So whenever there is a case diagnosed, this is usually pretty fortunate because we don't look at that many cows. It’s because a cow all of a sudden in the barn gets sick, and then there's all kinds of regulations thrown into place and people get worried for a while that similar cows are elsewhere are getting into the food supply. So clearly we need to have a good way of diagnosing the presence of prions. So we need to have a diagnostic test. We need to have drugs also, if we found a cow with prions in it, it would be nice to have a drug to block it. And of course in people, if we can diagnose prion disease in people, it would be nice to have drugs to cure the infection. So people are working on this and a couple of diagnostic tests have been developed. I told you one which is laborious and not likely to be of much use. But there is a second one which is pretty cool and I want to share that with you.

    21:18 This one can be done with either urine, recently it was found that prions actually excreted in human urine and we didn’t know that before, but in its original incarnation, the test was developed using nasal brushings. So it’s not the greatest test, because you have to put someone to sleep to do this, you lie them down and you put a long brush on the end of a long rod through their nose, all the way up to their olfactory neural epithelium, that's where your smell receptors are, it's right next to the brain case. So you have to put this thing all the way up there, and of course if you are awake, you are going to sneeze and they can't do it, so they have to put you to sleep. They brush it and get a little bit of the cells, and we know that prions can come out, you know your olfactory receptors, they are up there in your sinus essentially, and they are hardwired through your skull into your brain so the prions can come out and you get some of them if you have a prion disease. Then you do an ingenious test, really, really cool. It’s based sort of in PCR.

    22:19 Go back and listen to one of our introductory lectures I believe it's microbiology where I explained polymerase chain reaction, where you can amplify really, really small quantities of DNA. Here we can amplify small quantities of prion proteins. We take a little bit of these nasal brushings. If prion, pathogenic prions are present, PrPsc, they will be present in an oligomeric form. So look in that diagram at the bottom, there is what is called PrPsc oligomeric seed, so the SC versions will make aggregates coming out of your nose and then you add to that some PrPc that you've made by recombinant DNA technology and then you incubate them. And if there's PrPsc there, it’s going to convert the PrPc to more PrPsc, and these aggregates are going to grow. And they keep growing, you incubate them, this is many, many hours of incubation, they get longer and longer. And then at a certain point you stop the reaction, you sonicate it. You give it high frequency sound and you break up these aggregates, why? So that you can add more PrPc and repeat the cycle and you amplify it this way. You start out with a little bit of PrPsc and then you can do many, many cycles like 40 or 50 cycles and eventually you get tons of PrPsc and you can easily detect it by that Western blot that I showed you. So this works pretty well. It has pretty high sensitivity. Now if you show up and you have dementia and cerebellar ataxia and you're acting weird, they will take some your urine and do this test on it and see if you have a TSE or not. It's a very, very exciting development.

    24:01 Alright so at some point in the future we will be able to diagnose prion diseases, we will be able to treat them. In the meantime, let me tell you a little bit about the species barrier and why this scares us as well. I told you before you can inject animals with prion proteins and give them disease. So for example, if you take hamster PrPsc and you inject it into a hamster; they will develop a prion disease. Same species, no problem getting disease. If you take hamster PrPsc and inject it into a mouse, no disease.

    24:33 Doesn’t work very well cross species. However, if you make a mouse that is transgenic for the hamster prion, it will work. So the moral of the story is, the sequences of the PrPsc in the host and in the donor have to be what we call isologous, same protein or same species.

    24:56 If you simply give mice, a hamster PrP gene or whatever gene for whatever species you want to inoculate them with, they will get the infection. So, there is a species barrier to transmission, which is good. Which seems at first glance that this means that the thing, the prion protein, doesn't go easily between species. Well you know with every rule you make in biology, it can be broken. That's the way things are and this one is broken too. And we know already and you probably should preempt this, that the BSE PrPsc has a broad host range, if I eat meat contaminated with bovine prions, I can get a TSE. So what happened to the host range? Well there are always exceptions. Clearly some prions overcome the influence of the primary sequence of the protein on the host range and that's scary.

    25:45 That's why we are worried about BSE. We know that cow prions can affect people, obviously cow prions have a broad host range. The other prions we are worried about are those in cervids.

    25:57 Cervids are wild animals like deer, elk and moose. They develop a prion disease called chronic wasting disease. On the left in this graph is a map of the US and Canada, those black and gray areas show you where prion diseases of cervids have been diagnosed in various herds, they're all over the US and Canada, they have also been found in South Korea. In the graph on the right shows you how the incidence of chronic wasting disease, CWD, has gone up over the years since 1965 to the present, so it is spreading, it is increasing. Why are we worried about this? So again cervids are moose, elk and deer.

    26:38 In standing herds, up to 90% of deer, so that's a deer on the left there and 60% of elk, that’s an elk on the right are positive for chronic wasting disease prions. That is a lot of animals.

    26:50 These are standing herds, you know, on a farm or something like that. However, in the wild cervids, it's pretty high too, 15%. And we don't know how it got there and it's obviously spreading, so we’re little bit worried about this. How do deer and other cervids pass this disease? Well they can shed it, it can sit in the environment for a while and go to another animal or it can be shed and spread directly to another deer. So let's explore how some of this works.

    27:19 Let's look at shedding first, how would deer shed prions? Well we know by studying deer in the laboratory, the velvet that covers their antlers can be contaminated, saliva, nasal secretions, skin, blood, milk, birthing matter, urine, feces, all of this can shed prion, it is pretty scary. The carcass, if a deer dies in the forest the carcass is infectious.

    27:43 Plenty of opportunities to shed the prion. How about the environment, what happens there? Lots of opportunities. There are hotspots where deers like to hang out, carcasses obviously, if there is a carcass, other animals are going to come and eat it. Scrapes and rubs, places where deer like to scrape themselves. Mineral licks, if you put out a block of salt, deer like to come and lick it. Wintering areas, captive facilities, these are all hotspots for transmission. How does the agent get moved? Does it go by water, dust, do scavengers pick it up, animals who eat the deer, predators, other insects, these are the things that are possible, but need to be examined. Soil, what happens if the prion is shed into the soil by deer feces or urine, does it stay there, does the infectivity change, does the stability change, does the soil matter. Very recently it was shown that you can put prions on plants and the plants will take it up and then you can feed them to another animal and they will get a prion disease. So plants take up deer prions, they remain infectious and they can be transmitted, that pretty scary. Finally the environment, what does it do? Is it oxidized, desiccated, freeze, does freeze, thawing make any difference, is it degraded in any way.

    28:56 So these are some issues that need to be addressed. And uptake, how would animals take up these prions? Well from deer to deer, it can go by oral lesions, it can be taken up into the nose, inhalation, oral ingesting, passing through the gut and absorption through the intestine and presumably other animals can take up these prions in a similar fashion.

    29:18 So we have shedding from a deer, either alive or dead, which can go to another animal by direct contact, saliva or mucus, or the deer can shed the prion into the environment and then it can be introduced in some way, perhaps via grass into deer, or into another animal.

    29:37 So what about the host range of cervid prions, let's do the experiment. Take a mouse; inject it with cervid PrPsc, what happens? No disease. That's good; there is a species barrier, so cervid PrP cannot infect the mouse at least. Let's take PrPsc and put it into a mouse that is transgenic for the cervid prnp gene, those mice then develop a TSE. Perfect so far, so the cervid PrPsc only works in animals that have the gene encoding the cervid prnp. Now what if you take a mouse and make it transgenic for a human prnp? So this is sort, we can't infect people with cervid prions right, so the next best thing is to take a mouse, give it the human prnp gene, inject the cervid PrPsc, no disease. That's a good sign. That suggests that people won’t be infected, at least directly by cervid prions, but this is a mouse and you know in animals, in experiments with animals you always have to worry, you can't always extrapolate the humans. So we still need to be careful. So it looks like cervid prions do not infect mice with a human prnp, but people worry about the possibility that cows may be infected with cervid prions in pastures. You can imagine a scenario where deer come to a cow pasture at night when the cows are gone, they can urinate and defecate or lick the grass and put prions on the grass and the next day the cows come and eat the prions and they will get infected and then the cow is put into the human food chain and we get cervid disease indirectly. So we can do an experiment to address this possibility.

    31:30 We take a cow and we inject it with deer prions and the answer is yes, the cows do develop deer prion disease. So again the species barrier doesn't exist between deer prions and cows, so theoretically, deer prions could get into cows, cause disease and get into the food supply. So obviously we need to develop drugs to cure these diseases and better diagnostics to make sure that this transmission doesn't occur. Meanwhile, even if you're not worried about chronic wasting disease, if you hunt, you should be careful and there is a website that you can go to that tells you all about how to take care of deer if you like to hunt them and bring them home to cook them, you shouldn't shoot or handle in any way a deer or an elk that is acting weird. You have to look at it, you can tell when they have overt scrapie or a prion disease, they walk weird and they look bad, their fur is matted and scraped away, leave those alone, don't shoot them because they're an easy target, because they might get you sick. If you do kill a healthy animal, when you take it apart in the field, which is the way you do this I'm told, I don't hunt so I don't know but I take their word for it, wear rubber gloves, don't use a saw to chop everything up, stay away from the spinal cord, don't open the spinal cord, don't open the vertebral column to get the spinal cord out, that's bad because that's where most of the prions are. Just take out the meat in the field and leave the rest there and stay away from brain, spinal cord, eyes, spleen, lymph nodes, these tend to have a lot of prions in them. Wash your hands when you're done and cook the meat well, even though as I said, it's not going to help to get rid of prions if they're already there. But it will protect you against other parasite diseases.

    33:20 Let's end up with a little consideration of where these prion diseases came from. In this slide illustrates a number of prion diseases of humans in different animals and tries to assemble some kind of a sequence. The panels that you see in blue are naturally incurring affections and the ones in red are transmitted. Let's start at the very top, where we have sheep, who develop spontaneously scrapie and pass it on to one another, so that was probably originally the first TSE to develop, we think it could have been passed on to deer, so if you go to the left of the sheep we have some deer with chronic wasting disease, that could also have been a spontaneous infection or it could've been passed on from sheep, because deer and sheep can often cohabitate the same pastureland. There is a transmissible encephalopathy of mink, if you go down one panel in red you see a mink there, possibly the mink ate some sheep or maybe even a deer and acquired it so it may not be a natural infection of mink.

    34:26 Below the sheep we have cows who we know started to develop a BSE by feeding them, an epidemic occurred, but it may have occurred before that, possibly by being fed awful from sheep.

    34:39 The cows could then pass it on to other cows by feeding cows to zoo animals and also capture of cows in the wild by other wild animals, we could've passed it on to the greater cats shown to the right of cows and your cat, your domestic cat, we know there's a TSE that affects domestic felines, acquired by eating food from cows that is contaminated with TSEs.

    35:05 Below the cow is a human, who probably, who we know acquired TSE from cows and those humans can transmit those TSE to other individuals by iatrogenic and transplantation processes, but human TSEs may have in fact originated independently and spontaneously, as shown at the lower left, that blue panel, years ago, possibly the first TSEs of humans were spontaneous and then they entered the human chain, via iatrogenic or transplantation procedures.

    35:38 So there may have been very few original TSE diseases that began as spontaneous TSEs, which were then passed on by infectious and consumption roots.

    35:51 So TSEs and prions are really interesting and I hope after listening to me talk them, you'll understand the two different assays for detecting prions. You will know why mad cow disease, chronic wasting disease, may be threats to the food chain and what we can do about this. You will understand the species barrier to prion infection and how we examine that experimentally. And you should be able to trace the possible origin of prion diseases.

    36:18 Thanks for listening and happy eating.


    About the Lecture

    The lecture Prions – Infectious Proteins With no Nucleic Acids by Vincent Racaniello, PhD is from the course Prions. It contains the following chapters:

    • TSE Diseases of Humans
    • TSE Pathogenesis
    • Prion Protein
    • Mad Cow Disease
    • Molecular Test for TSE Prions
    • Chronic Wasting Disease
    • Origins of Prion Diseases
    • Prions: Learning Outcomes

    Author of lecture Prions – Infectious Proteins With no Nucleic Acids

     Vincent Racaniello, PhD

    Vincent Racaniello, PhD


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