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Comment by colanderman | Hacker News Reader

Dumb question (Wikipedia was of no help), if amyloid beta looks and acts like a prion, why isn't it classified as a prion?

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Amyloid-Beta is a specific instance of amyloids, while prions are a class of amyloids:

>"Some amyloid proteins are infectious; these are called prions in which the infectious form can act as a template to convert other non-infectious proteins into infectious form." https://en.wikipedia.org/wiki/Amyloid

So if amyloid-beta is determined to be "infectious" (however that is done) then it would be put in the prion subclass of amyloids.

There is a huge misconception about what is meant by the word "prion". Get this... there is only one (1) prion protein! All mammalian prion diseases are directly related to the PRNP gene. People talk about Mad Cow, Kuru, Creutzfeldt-Jacobs, Chronic Wasting Disease, Scrapie, and a dozen other diseases like they are not all manifestations of the same underlying problem with PRNP gene variants. People talk about "prions" as a general category of proteins capable of causing chain reaction misfolding... which is indeed what happens with PRNP variants, but not a whole bunch of different proteins -- just those transcribed from PRNP (the prion protein gene). We will probably discover that other proteins do this to some extent, but it'd still be weird to call it "a prion" because it's not a proten encoded by the prion gene. Does that make sense?

You don't share any links, but how would you reconcile this with the claims that amyloids are widespread. I posted about it here: https://news.ycombinator.com/item?id=19129157

Is it really the case that PRNP (https://en.wikipedia.org/wiki/PRNP) is the only known amyloid to be infectious?

My comment wasn't so much on the biology, or whether other proteins could display 'prion-like' behavior; it was more so to clarify what I think is a misuse/misunderstanding of the word 'prion'. I say this as someone who perpetuated this misuse until a few months ago, after reading an article about 'prions' in the retina, and spent half the day trying to figure out what the prion protein was, only to discover there was a gene that encoded PRioN Protein (PRNP); that is, we have a specific protein called 'prion protein' PrP. So to ask whether something is a prion suggests a misconception, since that's like asking "is insulin a keratin?" or "is melanopsin an actin?", and the answer would be, of course not, since those are all names of different proteins. Now, asking whether some protein X has properties similar to PrP is a totally legit question (i.e. "is X prion-like?" = great question; "is X a prion" = probably a misconception).

Thanks. It is also not clear to me after a quick search whether any amyloid has been called "infectious" other than ones derived from the PRNP sequence. It is very interesting.

I'm telling you-- i went down the prion rabbit hole myself recently and the entire path is littered with misconception and inconsistencies in how the term "prion" is being used.

One place to start other than wikipedia is this cdc site that lists know prion diseases...

https://www.cdc.gov/prions/index.html

After some digging, I concluded that all the diseases they listed are related to PRNP. Please, please, correct me if I'm wrong.

I'm actually going to chat with a friend in a few minutes who is a postdoc at MIT studying protein (mis)folding, and said he could help clarify. (i'll relay any new insights...)

Follow-up -- Spoke with my postdoc friend who informed me there are basically 3 definitions of prion being used in the literature (outside formal reports, he contends that, just as 'epigenetics' evolved to mean nothing in particular, the term 'prion' could mean almost anything). The big three:

1. The purists say prions are protein-only infectious agent; and they have a strong case since the word prion was coined as an abbreviation for "proteinaceous infectious particle". However the specific prion protein underlying these various diseases were all turning out to be the same thing.

> This evidence has led to the now widely accepted prion theory, which states that the cellular protein PrP is the sole causative agent of prion diseases; there is no nucleic acid involved. The theory holds that PrP is normally in a stable shape (pN) that does not cause disease. The protein can be flipped, however, into an abnormal shape (pD) that does cause disease. pD is infectious because it can associate with pN and convert it to pD, in an exponential process--each pD can convert more pN to pD.

  What is a Prion - Scientific America
  https://www.scientificamerican.com/article/what-is-a-prion-specifica/

2. So they officially named this protein (drumroll) prion protein (PrP), and the PrP gene was named PRNP (PRioN Protein). Yep, there is literally a "prion protein". This protein called prion protein is probably like any other highly conserved protein, and performs important every-day cell stuff. So prion protein does not usually display prion-like behavior

Not confused yet? Don't worry, there is a 3rd definition that has taken shape...

3. Self-templating. The word "prion" or "prion-like" has come to mean any protein that display self-templating, and is usually talked about in conjunction with epigenetic inheritance. My postdoc buddy contends this 3rd definition is winning the useage war, and so when he hears "prion", he assumes "proteins that can fold into multiple conformations with some being self-propagating." A very clear example of this usage can be found in this article on yeast (and no, it doesn't involve PRNP analogs): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319070/

Interesting, thanks for the history.

You seem to be mixing terms a bit, so at risk of repeating things you know, I will explain what I am reading from what you've linked.

PRNP is the gene encoding for "the major prion protein." Several different errors in PRNP create versions of "the major prion protein" that can be folded in a way that is bad (the prion folding). However, that is not the only way in which the proteins can fold themselves.

When lots of these proteins stuck together in an 'amyloid' (starch-like) aggregation, a misfolded (bad) shape of the protein serves as a template, folding more and more instances of the protein into the bad shape.

We consider the shape to be 'bad' because it is associated with visible symptoms of disease.

It is the prion ('bad') folding of a protein which would be infectious.

There are lots of different proteins that create amyloids, but so far all symptoms of prion-type disease for which a cause has been found have turned out to be associated with errors in PRNP.

>"so far all symptoms of prion-type disease for which a cause has been found have turned out to be associated with errors in PRNP."

Thanks, this is an interesting new fact to me if true. Is there a source for it?

I don't mean a source proving there are no others or something else silly like that. I mean like a review article that mentions they couldn't find any publication about any amyloid beyond PRNP-derived ones being transmitted.

I can't give you a source like that. From the Wikipedia article on prions, it appears that several prion-based diseases are suspected, but that so far the only proven cause for such a disease has been the "major prion protein." In 2015 a hypothesis was advanced that multiple system atrophy (Shy–Drager syndrome) was caused by a prion form of the alpha-synuclein molecule. However, if any subsequent proof has followed, neither the wikipedia pages on prions or alpha-synuclein have caught up with that.

It does seem like Abeta and prions should be in the same class.

A possible practical reason to keep them separated would be to avoid having various safety committees at X research institution from adding dozens of barriers to already difficult Alzheimer's research. Doing work with prions is a little like doing B. anthracis (Anthrax) research in some places - having to deal with indestructible spores.

Not that those safety measures shouldn't be put in place, but it'd make Alzheimer's/Abeta research slower and more expensive. The jump from BSL-1 to BSL2+/BSL-3 is huge [0].

[0] https://blink.ucsd.edu/safety/research-lab/biosafety/contain...

This is what the author was wondering at the end of the article. The discovery blurs the line between the two. There is now the question if they may be the same thing.

Article:

What is the difference between amyloid and prions? Are they part of a spectrum? Are they one in the same? If not, what is the difference? Can what we’ve learned about the biology of prions help our efforts to fight amyloid dementias?

Another dumb question: If Amyloid beta is a prion, why is it so common for Alzheimer's to occur only later in life, while teenagers can suffer from BSE? Does it have a longer incubation period?

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