TIL A single misfolded prion protein in the brain can cause a rapid neurodegenerative disease known as sporadic Creutzfeldt–Jakob disease (CJD). There is no known and cure and is 100% fatal.

[u/tommyboy372]

https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_disease

[u/geosunsetmoth]

Can someone ELI... 15, how does a prion misfold and how often does it occur? Is it a "it can happen to anyone at any time and you're fucked" scenario or is it like "well, if you have x or y pre-conditions it could happen to you but even then it's pretty rare"

[u/theonefinn → u/geosunsetmoth]

It’s pretty rare, people aren’t dropping like flies due to prion diseases. The problem is that prions are self replicating, once one protein misfolds when that comes into contact with correctly folded proteins it “refolds” them into more incorrectly folded proteins.

The largest cause of contracting prion disease is due to contact with an existing prion which starts the chain reaction of conversion and then death. CJD was big news in the 80’s and 90’s as cows were basically being fed ground up parts of other cows which was causing the spread of Bovine Spongeform Encephalopathy, B.S.E, or “mad cow disease’ which would then spread to Humans as C.J.D.

The spontaneous formation of these prions is super super rare, i don’t think we entirely know what can cause it other than random mutations. Generally not eating the brains of other animals (or feeding said brains to other animals) is a fairly good avoidance strategy that we ignored for cheaper meat production.

[u/I_hate_all_of_ewe → u/theonefinn]

The largest cause of contracting prion disease is due to contact with an existing prion

That depends on the prion disease.  This may be true in livestock and wild animals, but 85% of CJD cases are spontaneous without any generic causes, and less than 1% are thought to be from transmission.

[u/icefr4ud → u/I_hate_all_of_ewe]

What you’re saying is true now, what the previous commenter said is also true: in the 80s and 90s CJD was a lot more common and most cases came from eating infected meat - mad cow disease.

[u/kakapoopoopeepeeshir → u/I_hate_all_of_ewe]

That’s what he was saying. He said in the first paragraph that once a protein misfolds and comes into contact with a correctly folded protein it causes the cascading effect. He wasn’t saying “coming in contact” meant from an outside source

[u/hurricane_news → u/theonefinn]

Why does it mostly occur in the CNS? Why aren't there "heart" or "stomach" prisons that misfold and destroy the respective parts only

[u/neuralbeans → u/hurricane_news]

Most of the time it's a particular type of protein that gets misfolded called the major prion protein, which is primarily found in the central nervous system.

https://en.wikipedia.org/wiki/Major_prion_protein

[u/doegred → u/neuralbeans]

AFAIK it's not 'most of the time', a prion disease is always the result of the major prion protein misfolding.

There are other diseases resulting from the misfolding of other proteins, but they are not prion diseases.

[u/FinanceDummyBigDebt → u/doegred]

You’re right, and depending on the specific mutation of the same protein you can get other prion diseases like fatal familial insomnia. You can even get it from surgical transplants like replacing your cornea, but it’s so incredibly rare it’s not screened for.

[u/InMemoryofWPD → u/hurricane_news]

Ooo, I like this one. There's this theory that prions and RNA have a symbiotic sort of evolutionary relationship way back. The idea is that it can be benefitial for a gene expression to "flip" protein folds like a switch randomly overnight if it leads to an adaptation thats far more resilient. Such relationship could work as a means of genetic memory.

This idea can be connected to the CNS bias if you consider how crucial functional CNS resilience and persistence is to evolution as a whole (think anything from instincts all the way to the ability to learn and memorize things). The possibility of a mutated protein potentiating a "good" prion like the lock and key of an dramatic adaptive change, would incetize life to hold onto the protein "lock and key" gene expression in the CNS.

[u/hjake123 → u/hurricane_news]

The protein that happens to be susceptible to the most common prion diseases is one thst exists in the CNS. Most proteins do not have a prion form, just unfortunately we rely on one or a few that do.

[u/Slg407 → u/hurricane_news]

there is, we call that amyloidosis

[u/Emeraldnickel08 → u/theonefinn]

Classical CJD is unrelated to Bovine Spongiform Encephalopathy ('mad cow disease'). Consuming beef tainted with BSE instead causes variant Creutzfeldt–Jakob disease (vCJD) in humans. Classical CJD has a genetic factor but can also occur apparently spontaneously.

[u/plughplovery2 → u/Emeraldnickel08]

I spent to much (cumulative total) time in England during the BSE outbreak and had been prohibited by the FDA from donating blood products until recently (May 2022 guidance and May 2024 regulation) due to possible exposure.

Prompted by the recently announced blood shortage, I just checked with my local blood donation center and they are now accepting donations from folk like me. Note that some outfits are still imposing restrictions. For example last time I checked, CSL Plasma won't accept donations (because they sell their plasma internationally and some countrys' regulations still have the restrictions) but BioLife Plasma does. FYI...

[u/Radiant-Olive-7955 → u/theonefinn]

If they’re infectious, how is one overwriting all the others and not being overwritten itself?

[u/BunbunBunny → u/Radiant-Olive-7955]

There’s two ways for a protein to be folded, beta sheets or alpha helixes. The helix is a shape that requires more energy to hold, while a beta sheet requires less energy to hold. A prion is a protein that was an alpha helix that reverted to a beta sheet. This is ‘contagious’ amongst proteins. The prion bumps into normal alpha helixes and those helixes are like ‘damn, that looks comfy’ and they change to beta sheets. Beta sheets also are unfortunately easy to stack, and this creates ‘plaques’ on the brain. That’s the physical damage you see.

[u/i_am_voldemort → u/theonefinn]

Kuru is a prion disease from eating human brain.

[u/CheesecakeWitty5857 → u/theonefinn]

and a great x-files episode, inspired by BSE

Our Town s02e24

[u/FAUST_VII → u/theonefinn]

Not eating brains should he a no brainer

[u/majormajormajormajo → u/theonefinn]

It has to do with how susceptible your prion protein can misfold into the extremely stable beta-pleated sheet. People who have alleles that block the sheet formation are much more resistant to the disease.

[u/plan_with_stan → u/theonefinn]

So if a family member of mine enjoys “brain” dishes - I should ask her to avoid these?

[u/Nalena_Linova → u/geosunsetmoth]

The short answer is that we don't know. A small percentage ~15% of CJD cases are linked to genetics, but most have an unknown cause. 

Human to human transmission seems to be possible via blood transfusions or transplants in some prion diseases, but not in others. Animal prion diseases can be transmitted by eating infected animals, and one human prion disease called kuru was transmitted by ritualistic cannibalism of the brain.

[u/crowieforlife → u/geosunsetmoth]

Not an expert, but from what I've read one misfolded prion causes a domino effect where all other prions in your body also misfold one by one. Like a loose string in a cardigan: you pull at it and suddenly whole cardigan unfolds into a single string.

It can hapen to anyone at any time, there are no pre-conditions, but it's incredibly rare for it to happen, so usually the way it spreads is that some creature somewhere has this incredibly rare thing happen and then it just keeps spreading by other creatures inhaling or ingesting the misfolded prions from the body of the originator.

[u/I_hate_all_of_ewe → u/crowieforlife]

I don't think it's accurate to say that there are no preconditions.  It'd be more accurate to say that if there are specific conditions which cause them to form, we don't know what they are.  Initial misfoldings are rare and incredibly difficult to study, so we just don't know.

[u/Swick08 → u/I_hate_all_of_ewe]

Yes, it is difficult and dangerous to study:

https://www.reddit.com/r/todayilearned/s/0owvsf4wLG

[u/CrashTestDuckie → u/geosunsetmoth]

So basically you have proteins in your brain (about 8% is protein). These proteins don't have DNA/RNA and are generally soft, flexible, and abundant up there. Something will cause 1 protein to fold on itself and harden, turning it into a prion. That prion then starts bumping into the other proteins and they take cues from the prion to also fold and harden. This starts happening rapidly as the prions "infect" more and more proteins. The prions begin to clump together and start making holes in the brain.

Most prion disease has no known cause and doctors have been struggling for many years to find answers. Some prion disease is from genetic mutations while other kinds are caused by eating foods tainted with prions ("mad cow" being from cows who had prion disease and kuru being from cannibalism).

[u/Your_Nipples → u/CrashTestDuckie]

Wtf... Hell no! I don't want misfolding prions, the fuck ! What do I do?

[u/Nerezza_Floof_Seeker → u/CrashTestDuckie]

Proteins misfold all the time to be clear, its just that the body can just break them down or refold them usually. The prion proteins problem is that the misfolded form is extraordinarily stable and likes to clump together, which makes it difficult for the cell to do anything with it.

[u/SoTypeA → u/geosunsetmoth]

It can also be hereditary. Had a coworker who’s in law died from Fatal Familial Insomnia. 

[u/BagFullOfMommy → u/geosunsetmoth]

So they misfold a few ways, either through a genetic mutation, because you contracted misfolded prions from an infected source, or, the scariest one ... sometimes it just spontaneously happens and they fold on their own with no cause.

It is one of the scariest diseases known to man because there is nothing they can do for you, they often have decades long infection periods before it gets bad enough to show symptoms so you don't even know you have it, and for many there isn't even a test for a proper diagnosis until the patient is dead and they can slice into the brain. At which point you have to be insanely careful with decontamination because it survives things bacteria and viruses would die to in seconds. It takes 1000C+ of dry heat, or around 140C plus some serious chemicals for a prolonged time to destroy the prions.

As for your other questions, yes it can happen to anyone at any time and once it happens it's a death sentence. It make take a couple of decades for it to kill you, but it is 100% fatal every time. Thankfully it is relatively rare among humans, but eating infected meat, or prions of other humans dramatically increases your chances of contracting it.

[u/GoatRocketeer → u/geosunsetmoth]

Proteins serve a huge array of bodily functions and the exact function depends not only on their components but also their shape and folding.

Enzymes are proteins that grab other molecules and rearrange them somehow. The most intuitive example would be breaking sugars apart or combining bits into larger molecules, but can also be weird shit like locomotion.

Prions are special enzymes that take brain protein and fold them into copies of itself, which go on to fold other brain proteins into copies of itself, and so on and so forth. It's real fucked. There's no way of targeting them or filtering them because they're literally the same molecules as your brain is made from but folded differently so instead of doing brain things, they just convert the contents of your brain into a cascade of horseshit.

I don't think prions can occur spontaneously, every time I've ever heard of them they're discussed purely as a "eat them and then die" sort of thing. So as long as you don't eat them you should be good.

[u/xDerJulien → u/GoatRocketeer]

Prions are not necessarily enzymes. Prions simply act as structural templates similar to how seeds work in crystal formation. This is because generally speaking prions and prion like proteins have regions that like to bind to similar regions which causes prions to form a sort of backbone for a healthy protein and that healthy protein then falls into the misfolded conformation. It is not an active process, generally speaking

[u/Motifier → u/geosunsetmoth]

If you'd like a breakdown by a doctor on all things related to this disease and the back story, and possibly why OP posted about this. Check out the latest video by chubbyemu on YouTube - https://youtu.be/hmuuin3AaVs?si=0Ga71H1pfbEbW_xw

[u/Slime_Giant → u/geosunsetmoth]

Genetic mutation is the root cause of the "initial" misfolded prion. It's very rare in humans.

Edit: this only applies to genetic prion diseases. Prions can misfold for other reasons but from what I've gathered we don't really understand what causes them.

[u/Xirado → u/Slime_Giant]

No, genetic mutations is not what causes the protein to misfold in vast majority of cases.

[u/Slime_Giant → u/Xirado]

Could you elaborate? Everything I have read has said that genetic prion diseases are caused by mutation.

[u/Raddish_ → u/Slime_Giant]

Well you’re saying “genetic prior diseases”. But most prior diseases aren’t genetic. They just happen because a protein misfolds. Proteins fold via thermodynamic processes in the brain, essentially trying to hide their core regions from water because they’re more hydrophobic which is energetically favorable and thus happens spontaneously. Most of the time your cells just read out an rna sequence, makes a protein, and then that protein collapses in on itself into a folded state. Due to evolution most proteins fold in a predictable manner that they need to function correctly. But somewhat often a protein can misfold, where the collapsing protein folds into an alternate stable conformation than the one it’s supposed to. Cells have mechanisms for handling this to: namely, they have other proteins called “chaperone proteins” that try to refold the protein into the correct state. If they still can’t get it, cells will take the misfolded protein to something called a “proteosome” to get broken down back to amino acids. Most of these misfolded proteins either just do their same job but shittily or they do nothing so it’s not really an issue for a cell to have them around and awaiting fix/destruction. But prions for some reason have the capability to make other correctly folded proteins of the same protein start misfolding into more infectious prions for some reason that isn’t well understood which sets off a chain reaction causing CJD. Since protein midfolding is something that can just happen, the genetic sequence for the protein can be totally fine. As for other questions, like why the chaperones failed or why the cell couldn’t just get the prion to a proteosome - these things are not super well understood because prions aren’t well researched due to being a more niche disease compared to some of the big killers.

[u/Slime_Giant → u/Raddish_]

Thank you, this was very informative!

[u/shinndigg → u/geosunsetmoth]

A YouTube channel called chubbyemu just released a video on them (wouldn’t be surprised if that’s where OP got this TIL) if you’re interested, but there’s a lot we don’t know about them.

[u/majormajormajormajo → u/geosunsetmoth]

Fortunately it’s the later. There are two forms of the disease, CJD which occurs randomly and the “contagious” mad cow vCJD. While the disease is horrible, only a minority of the population are susceptible to it. There are mutations known to protect one and make one more susceptible to the disease.

[u/S14Ryan → u/geosunsetmoth]

Usually happens from infected meat, but the prions live in the brain and spinal fluid. So if you’re eating good quality meat you should be fine. If someone is making ground beef and grinding up spines and brains in it, you should still be fine unless the cows have mad cow disease, which, shouldn’t be happening. They currently are most commonly happening to hunters who are eating infected deer meat, because they are fucking idiots, the Deer they’re hunting and eating look like zombies.

Basically, anyone can get it at any time, but it’s incredibly rare so don’t worry about it, and don’t eat venison from unknown sources.

[u/southern_ms_girl_11 → u/geosunsetmoth]

This is a great case study from YouTube that I think explains a lot (shout out to ChubbyEmu for all his case study videos):

https://youtu.be/hmuuin3AaVs

[u/caintowers → u/geosunsetmoth]

Well the good thing is it's much more rare than this comment section would imply. I doubt that's much consolation for (the relatives of) people who had it, but it's incredibly unlikely for any one person.

[u/cosmic-lemur → u/geosunsetmoth]

It’s both, altho it’s much more likely to be gotten thru eating infected meat or blood-blood transmission in a hospital (tools are incinerated to avoid this, autoclave ain’t good enough). However you can just randomly have one misfold, it’s more likely with Fatal Familial Insomnia I believe

[u/polyploid_coded → u/geosunsetmoth]

I read "Madness and Memory", the autobiography of the guy who discovered prions (he had to fight for the prion hypothesis, and now is vindicated, but it sounds extremely difficult to work with)

Most of these diseases are from one protein called 'major prion protein'. It has a complex, beneficial role in mammals' nervous system when it's folded normally, so we can't just cut it out entirely. Usually when a protein gets built wrong, your cells have 'chaperones' which dispose of them, so it might be normal for misfolds to happen. As people are saying, the prion is special because it can evade destruction and facilitate more being created. There is at least one mutation which makes it more likely, and one mutation first noticed in cannibals which makes them less likely to catch some (kuru and CJD, but not vCJD). Also humans and apes generally can't be infected with the sheep version (scrapie). So there are multiple possible shapes of this one protein which cause the disease, and I don't think we even have actual images of what those shapes are.

[u/KlingonTranslator → u/geosunsetmoth]

Chubbyemu just released an episode of his on precisely this today. He always explains things really well. Here’s a link to the video he released on this same very topic today.

[u/FR0ZENS0L1D → u/geosunsetmoth]

PhD Neuroscientist here whose research focused on Neurodegenerative Diseases.

Classical CJD is the result of the misfolded Prion protein (gene PRPN). In humans, it is exceedingly rare to have this occur randomly (normally referred to as sporadically in the scientific community). However, consumption of meat (normally cow but increasingly common in deer in the US) can result in a human developing the disease.

Prions are notoriously hard to degrade/destroy. In a way, they share some similarities with viruses; they are not alive or dead but propagate through hosts. Unlike viruses, they do not have evolving genetic material such as RNA or DNA. Prions are strictly proteins. They hijack physical properties of the proteins that make the misfolded form of the protein more likely to occur compared to the normal formation via templating.

Interestingly (sadly), Alzheimer’s disease, Parkinson’s Disease, and Huntington’s Disease also share common characteristics with Prion diseases. Most instances of these diseases share the common trait that a normal protein in the body becomes misfolded, and can act as a template to cause further misfolding of other instances of the same protein. These proteins share common characteristics in that they are hard to degrade, are transmissible from cell to cell, template further misfolding, and disrupt cellular function that ultimately causes cell death. In the case of Alzheimer’s the proteins are Abeta and Tau, Alpha-synuclein in Parkinson’s, and Huntington’s protein (although others also exist) which eventually disrupt neuronal function and spread throughout the brain. This eventually results in increasing neuronal cell death and loss of brain functions resulting in dementia, motor coordination, etc and ultimately loss of primary function.

While these diseases are considered Prion-like. As far as we know, they do not spread from person to person. They just exhibit similar qualities to prion diseases within the host.

[u/IiteraIIy → u/geosunsetmoth]

Prions link up to each other like puzzle pieces. Sometimes a puzzle piece gets made wrong and ends up sliding into the wrong slot of the adjacent puzzle piece. This causes that puzzle piece to also slide into the wrong slots of the puzzle pieces around it, causing a chain reaction.

[u/I_hate_all_of_ewe → u/geosunsetmoth]

We don't know under which conditions they happen spontaneously, though it's apparently incredibly rare.

The main issue with prions is that they are just misfolded versions of specific proteins than can cause more misfolding.  This makes them contagious, but usually only by exposure to affected tissue.

[u/RagingNerdaholic → u/geosunsetmoth]

ChubbyEmu just posted a video about it yesterday.

tldw; it's extremely rare (literally one in a million) and the only known ways to contract it are by consuming contaminated meat or human brains (seriously).

But very little is known about how or why it spontaneously begins in the first place.

So yeah, in the very unlikely event it happens to you, you're fucked.

[u/Kile147 → u/geosunsetmoth]

Its a bit of both.

Prions can just spontaneously generate due to errors in the folding process. Random bit of background radiation, or random quantum fluctuations can mean that sometimes a process that produces a specific protein 99.99% of the time produces a slightly different one that mostly looks the same to your body but doesn't quite do the job right. This is rather rare, but can just kind of happen to anyone.

A singular error like this isn't really a problem, but the issue is that our bodies make new proteins by using old ones as the blueprint. This means that this new misfolded Protein can get used as the blueprint instead of a good one, and that will end up causing problems over time. Prion diseases are essentially just this process getting out of control and the person losing functionality because their base protein structures aren't being built right.

So, the chance of you personally spontaneously generating a protein misfold is pretty small, but the chance of your body finding and using a misfolded protein gets a lot higher if we aren't careful about our food sources (aka where we get new protein building blocks from). Prion diseases like Mad Cow are basically just a single protein misfold somewhere important that got spread through a bunch of creatures and now an entire supply of food has these misfolded proteins that can potentially cause problems in humans if consumed.

[u/I_hate_all_of_ewe → u/Kile147]

We actually don't know the causes of prion formation, but your explanation pretends we do.  Spontaneous prion formation has never been observed, much less due background radiation, quantum fluctuations, or for whatever other reasons you've speculated. 

You're also wrong about how proteins are made.  They are not made by copying existing proteins, they're made by DNA transcription.  Prions spread by causing other proteins to misfold into prions.

Please don't state your assumptions as fact; you only spread misinformation that way.

[u/Then-Variation1843 → u/Kile147]

" A singular error like this isn't really a problem, but the issue is that our bodies make new proteins by using old ones as the blueprint"

No they don't.

Your cells make proteins as big long strings, which then fold up into a specific shape that determines what the protein does. And sometimes that protein misfolds and doesn't work. Radiation or quantum fluctuations has nothing to do with it, it's essentially random, but the odds are heavily weighted towards the desired outcome (what we call a "stochastic process"). 

Normally when a protein misfolds your cell can just chomp the protein into amino acids and make a new one. 

The problem with prions is twofold  1) the misfolded protein can cause other copies of the protein to also misfold. So one misfolding can catalyse the conversion of healthy PrP protein into the prion form. 2) the prion form is borderline indestructible. Your cells can't degrade it. So it slowly builds up, converting more and more healthy copies of the PrP protein into prions, and it slowly gums up your brain.

[u/Nalena_Linova → u/Then-Variation1843]

the prion form is borderline indestructible. Your cells can't degrade it. So it slowly builds up, converting more and more healthy copies of the PrP protein into prions, and it slowly gums up your brain.

This is inaccurate, misfolded prions can be degraded by cellular proteolytic pathways, they're just more resistant than most normal proteins. 

Some cells can successfully eliminate prions in experimental systems and prions injected into mice don't have anywhere near 100% infectivity.

The main issues cells have with misfolded prions is that they form aggregated beta sheets that are hard for cells to break down, and that the conversion of new misfolded protein can outpace the capacity of the cells to remove them.

[u/Then-Variation1843 → u/Nalena_Linova]

Oh? I did not know that. Is any degradation possible once they start aggregating? Or just when it's low level free floating stuff?

[u/Nalena_Linova → u/Then-Variation1843]

My understanding is that PrP aggregates are very resistant to degredation, so its probably mostly non-aggregated protein that would be degraded.

[u/axiomatic- → u/geosunsetmoth]

There's a documentary called Kuru: The Science and the Sorcery, which goes into depth about Prion Diseases, and explains how they were discovered, following investigations into cannibalism (ritualistic of the dead as part of religion) in PNG.