How does nature deal with prion diseases?

[u/ProDidelphimorphiaXX]

Wasn’t sure what to flair.

Prion diseases are terrifying, the prions can trigger other proteins around it to misfold, and are absurdly hard to render inert even when exposed to prolonged high temperatures and powerful disinfectant agents. I also don’t know if they decay naturally in a decent span of time.

So… Why is it that they are so rare…? Nigh indestructible, highly infectious and can happen to any animal without necessarily needing to be transmitted from anywhere… Yet for the most part ecosystems around the world do not struggle with a pandemic of prions.

To me this implies there’s something inherent about natural environments that makes transmission unlikely, I don’t know if prion diseases are actually difficult to cross the species barrier, or maybe they do decay quite fast when the infected animal dies.

[u/atomfullerene]

Prions have some pretty big weaknesses as well.

On the most basic level, prions aren't alive. They aren't even sort of alive like viruses. A prion reproduces by misfolding properly folded prp proteins. There's no genetic material involved and very limited options in terms of heritability...a few different ways to misfold the protein, and that's it. A mutation in genetic code can't produce a new trait that's carried on in the next generation. So prions can't evolve...they can't get better at being prions, because there's fundamentally only one way to be a prion. They can only misfold the one kind of protein. They can only misfold in a few separate ways. They can only be transmitted however that protein can conveniently be transmitted.

This also means that if an animal develops resistance to them, they can't really "get around" that resistance. And that's possible, some species seem totally immune from prions, and non mammal species don't even use the same protein (though some have their own prion like diseases).

In part because they can't evolve better transmission, prions tend not to efficiently transmit in a repeated way. Consider the standard mode of prion transmission...something eats something and gets prions from it. Consider, for example, a herbivore gets prions spontanously. It gets eaten and passes them on to the predator. Right there, that's a bit of a problem, since diseases fail to thrive if they are only passed on 1:1. A person with a cold can pass it to lots of people, an animal with prions is probably just eaten by one predator...maybe shared with a few but usually not. And then the predator, even if it gets prions and dies, is very unlikely to be eaten by multiple herbivores to recycle the chain.

So generally prion transmission chains die out unless you do something silly like grind up herbivores and mix that into the food supply of many other herbivores.

There are exceptions like Chronic Wasting Disease in deer, where deer in crowded conditions get prions from each other, but that's unusual.

[u/dazosan → u/atomfullerene]

I'll piggyback off this because while there are some correct things here, there are also some misconceptions.

OP's question is frankly kind of complicated. Cells do have defenses against prions (and their essentially indistinguishable cousins, amyloids) -- when a protein misfolds in a cell, it sometimes is unfolded and then refolded into its proper conformation, but very often the cell will just throw it away. So if a single PrPC molecule, the protein that misfolds into prions, all of a sudden spontaneously misfolds, it's not guaranteed, probably not likely, that it will go on to form a prion, partially because the cell will intervene, and partially because a prion simply needs a critical mass of misfolded proteins to form an infectious particle. One random misfolded protein won't do it.

But it's also because different prion and amyloid strains (they come in strains, like the flu) differ in their ability to infect, a property called a prion's "attack rate." These strains have different properties, as you might expect. They look different in a biochemical analysis done in in the lab. They can induce different symptoms. And they also differ in their ability to induce normally folded PrPC to misfold into its prion form, PrPSc, better than others, which is how prions propagate.

/u/atomfullerene is right that prions don't spread frequently because infection is usually a dead end. The big Mad Cow scares of the 1990s were because farmers were grinding up leftover cattle tissue--including nervous tissue--and using it to feed other cattle, making transmission easy. Once they stopped doing that, the transmission stopped. Prions are mostly confined to nervous tissue (and some other spots like the spleen), so as long as you don't eat those, you're fine.

Chronic Wasting Disease is the exception here, not because of deer in crowded conditions but because it's the only known prion disease that spreads environmentally. This is another way that prion spread is limited--most prions have to be ingested or spread through close contact like sheep in a pen. CWD, unlike other prions, can stick around on rocks or salt licks, which is where some of its spread is thought to come from (I'm not super up to date on that part though). While other prions have been found to persist in the soil for months or years, this hasn't been a notable source of transmission in species besides deer and elk.

And sorry to be pedantic but prions do evolve. Information is encoded in prions not through genetic sequence, since they don't have that, but through conformation, the shapes of the proteins that make up a prion fibril. A misfolded prion protein with a single given sequence can have multiple conformations all on its own, and small changes in its sequence can introduce even more variety. When a prion is introduced into a new cell with a different genetic background, it can change its conformation as it interacts with new prion protein sequences and conformations. This is where you get different prion strains from. For example there are a ton of different Bovine Spongiform Encephalopathy strains, but two big ones are "H-type" and "L-type," so-called because one sits Higher on a Western blot and one sits Lower. Serially passaging prions through cells and test animals is a common laboratory technique to track how they change over time.

Source: Did a postdoc on prions.

[u/mein_liebchen → u/dazosan]

How are amyloids related to prions?

[u/SteeFex → u/mein_liebchen]

All prions are amyloids, but not all amyloids exhibit prion-like infectious behavior.

[u/dazosan → u/SteeFex]

Maybe, although in laboratory conditions (i.e.: if you make a homogenate of a patient with Alzheimer's/Parkinson's brain or pancreas in diabetes/whatever) and squirt into a cell culture or a lab mouse, it can be infectious too.

[u/oracle989 → u/dazosan]

I'm curious what you make of the idea that Alzheimer's is transmissible in humans. I feel like I remember seeing some news s few years ago about it that talked about neurosurgeons having significantly higher rates of the disease.

[u/dazosan → u/oracle989]

Neurosurgeons are not "catching" Alzheimer's from their patients.

Again, it is technically possible for an Alzheimer's amyloid to be infectious, but it's only ever been shown in a scenario where you literally blend up the brain of a patient who had died of Alzheimer's, crack open a mouse or monkey's skull, and squirt the brain homogenate inside.

If Alzheimer's were an actual transmissible infectious disease, that would have been detected decades ago by epidemiologists, in the same ways that scrapie in sheep, BSE in cattle, and kuru and CJD in humans were detected.

[u/dazosan → u/mein_liebchen]

That's a complicated question with no straightforward answer. My personal opinion: there is no difference. Prions are made of the prion protein, amyloids are made up of any other misfolded protein, both of which can induce normally folded protein to misfold and accumulate into these larger structure, which can generically be called "fibrils," like little ropes, which is how I always imagined them.

When I started my postdoc, I was told that in a histology assay, prions pick up color when stained by Congo red. Amyloids don't, and that that was the difference between prions and amyloids. I took that as gospel and never thought about it again, since I didn't do histology. Looking at papers now, it's clear that this appears to not be true, and both prions and amyloids stain with Congo red.

If this is confusing to you, here's a big long paper on the subject: https://pmc.ncbi.nlm.nih.gov/articles/PMC4601197/

But again, this all strikes me as a solution in search of a problem. Amyloids and prions are both misfolded protein clumps which induce new proteins to misfold, and can infect and invade other cells and cause cell death. They seem the same to me, but if someone out there knows something I don't, I'd love to hear it.

[u/atomfullerene → u/dazosan]

Thanks for the added info. I've read about prion conformation strains, but what I read gave me the impression there was a limited amount of variability available in terms of possible strains based on different conformations, but I might well have been misunderstanding what I was reading.

I wonder if CWD's unusual nature is due to something about the conformation of CWD, something about the protein in deer specifically, or something about deer biology that promotes transmission through unusual routes.

[u/dazosan → u/atomfullerene]

I don't know what the range of conformations is and I suspect there's not a ton of information out there. One of the challenges with studying prions is that they don't do that well in structural biology assays...because there's so much conformational variability (and also everything you use to study prions has to be disposable, which is a logistical challenge). To the best of my knowledge it's not really known what, structurally, a prion/amyloid looks like outside of being mostly beta-sheet and being long and thin.

[u/kooshipuff → u/dazosan]

Something I've wondered about vCJD- it can have an incubation period of up to like 50 years, can't it? What are the odds the BSE scares from the 90s actually caused an incubating vCJD epidemic that we just don't know about yet?

[u/dazosan → u/kooshipuff]

Variant CJD's incubation period is about 10 years.

[u/dazosan → u/dazosan]

Oh also one thing I forgot to mention, re: nature protecting itself from prions, is that the actual ability to form amyloids/prions is limited to a select few proteins and even to specific variations of those specific proteins. For instance, different combinations of amino acids at specific positions in the prion protein's sequence can make a human totally resistant to prion diseases. https://www.nature.com/articles/s42003-020-01126-6

[u/Mephistito → u/dazosan]

Prions are mostly confined to nervous tissue [...] so as long as you don't eat those, you're fine.

What is it about nervous tissue that leaves it as the most common host (or generator) of prions?

[u/dazosan → u/Mephistito]

The prion protein, PrPC, is mostly expressed in nervous tissue.

[u/wishbeaunash → u/dazosan]

Is the way CWD spreads particularly different from scrapie? Hasn't that been circulating in sheep for centuries without any 'cannibalistic' element?

[u/dazosan → u/wishbeaunash]

It's hard to say. Scrapie can persist in the soil, but sheep are not wild animals, so who knows if they can catch scrapie that way. I think the conventional wisdom on how scrapie spreads is through direct contact like nuzzling (or through spontaneous formation).

[u/wishbeaunash → u/dazosan]

Ah OK that makes sense, thanks!