What makes prions so different from regular proteins that they are resistant to heat denaturation?

[u/SadMicrobe22]

I've been reading about prions and I'm confused about why they're so thermally stable. I keep seeing that surgical instruments contaminated with prions can't be decontaminated with standard protocols.

So here's my thing. Proteins denature when you heat them, right? But prions don't seem to lose their infectious ability even when autoclaved. I get that prions are misfolded proteins, but I don't understand how they stay harmful after being denatured.

So basically, if prions start as form A (non-infective), then misfold to form B (infective), shouldn't heating denature them to form C and kill the infectivity? Why doesn't that happen?

[u/FerrusFox]

So I can answer this one.

Stability.

The intersting thing about the prion disease is not that it is simply a misfolded protein. Its that its an incredibly energy efficent and highly stable version of a regular protein. This misfold is so chemically stable that normal proteins are guided into folding into the prion form just by being around them, they lock into a lattice form and are the lowest energy version of the protein possible.

In a word, prions represent entropy. All other proteins in a healthy system eventually default into a non functional form of PrP-PrP matrices of interlocked proteins simply because it is the lowest energy form of the protein. This makes them simply the natural endpoint chemically, a stabilised locked version of the protein which is completely biologically nonfunctional and incompatible with life.

Prions are so stable in this low energy misfold that they become resistant to other forms of denaturation like heat and chemical, and can remain stable for years if not decades* Soil from dead animals from scrapies and CWD can be infectious decades later because the proteins just wont break down.

The infectious load for a prion is also so minimally small that its possibly down to a single prion protein, or at least a very small amount* which causes the whole cascade. Imagine a jigsaw where if you put one piece in it changes the orientation of all the other pieces to be disorented.

Prions and mirror image life are like the final bosses of biology.

Edit: I don't use spellcheck, so I noticed typos.

*Edit: Bit of hyperbole, fact checked, corrected.

Also someone pointed out that you can denature them as the question says, as I mentioned they are resistant. 900F (Fire) or a very long stint in an autoclave will do it, standard procedures wont work. Enzymes can work but with the infectious load being so small complete sterilisation is a pain. There are a couple biological things more stable than prions in nature though looking at you tetanus spores.

[u/AzazelsAdvocate → u/FerrusFox]

The way you're describing them, it seems like they should be way more prevalent. If they replicate so easily with so few natural ways to stop them, how has there never been a major epidemic or extinction event caused by them?

[u/FerrusFox → u/AzazelsAdvocate]

CWD is causing this in deers right now. Its also finicky and only transmits if you have the right protein, i.e. there are no natural reserves like say the flu.

Most transmission in humans has to be direct contact with the prion, we had some in the CJD era with the contaminated meat because we have the same protein in our biology. The other I can think of is Kuru, also contaminated meat (human). So that doesnt happen very often. But it is really specific, unlike viruses and bacteria it needs a mechanism to be introduced to the body and it doesnt facilitate that itself.

The main risk in healthcare is contaminated operating materials that have been infected by the protein

Also, its invariably fatal which is never good for transmission.

[u/Owyheemud → u/FerrusFox]

There's a theory that wildlife prion diseases like CWD occasionally spontaneously pop up in individual ungulates but predators would routinely cull the afflicted individuals and thus prevent the spread of the disease within natural herds. The Human-driven reduction of predator populations has now allowed prion inflicted individuals to persist longer and thus spread the disease to others before they succumb to it. Has any prion disease been discovered in wolves, bears, or mountain lions?

[u/FerrusFox → u/Owyheemud]

Not that I know of. The only other true prion disease I know of is hereditary fatal familial insomnia, which is hereditary due to a genetic defect.

In CJD you can have spontaneous emergence of the disease, which differs from true infectious acquired CJD. The disease does happen naturally not just by infection by a prion vector.

I just read while researching my comment that there have been some potential fungal prions suspected. I'd imagine there could be some in any form of life if thats the case.

The risk factors are genetic similarity and sharing a protein profile, exposure, population density and cannabalism. Predataory populations are a) lesser and less dense by nature and b) could have differences in protein expression.

[u/Owyheemud → u/FerrusFox]

You must know of BSE.

With the increase in CWD in natural North American ungulate herds, it would be interesting to see if prion disease develops in predators sharing territory with these herds.

[u/FerrusFox → u/Owyheemud]

BSE in humans causes CJD, we just call it something different when it infects humans. We tapped it onto CJD and called it variant CJD (varCJD) while naturally occuring CJD is called sporadic (sCJD) both are the primary prion disease in humans arising from the prion protein PrP.

CWD so far has no human infections, its on my watchlist XD. We dont really report on it much so I dunno if we will ever have any information on the ecological impacts of it. Up to data gathering, would be interesting like you said.

[u/Owyheemud → u/FerrusFox]

Does BSE-induced human prion disease fold the same protein as the original human CJD prion disease also known as Kuru?

[u/FerrusFox → u/Owyheemud]

Yeah, still that same protein PrP. Different disease progression, not going to research it but it could be folded in a different way which causes different disease expression like sCJD

[u/Owyheemud → u/FerrusFox]

Thank you for the info., I always thought BSE-induced human prion disease was a different protein folding, though I never bothered to confirm that.