Eli5: As I understand, a prion is a misfolded protein. How does misfolding apparently give it the ability to break everything?

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Eli5: As I understand, a prion is a misfolded protein. How does misfolding apparently give it the ability to break everything?

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The key to prion diseases is that the misfolded protein also causes *other* proteins to misfold. So instead of just one rogue protein, you get an exponential growth of bad proteins, pretty much exclusively leading to death.

Proteins can be folded into enzymes which act as both a holder and tool to make certain chemical reactions, like breaking or fusing molecules, easier.

Prions are misfolded proteins that act like enzymes to take a certain protein and change them to the misfolded prion shape. It’s like a hammer that hits pieces of metal into more of the same hammers.

One misfolded protein is fine, you cells will destroy it. But prions are worse. They will literally touch another protein and force it to misfold. The new misfolded protein can now also go and touch other proteins and make it misfold. This exponential reaction will misfold nearly every protein in your entire body within a few weeks. No good protein = no bodily functions = death.

If this kinda sounds similar to how viruses and bacteria infect cells, you’re right. That’s why some people think of prions as “infectious proteins”

The shape of the protein is what gives it its function. So, immediately, a misfolded protein is at the very least incapable of doing its function. As far as I can tell, the normal function of the specific protein that misfolds in CJD, the human prion disease, isn’t known yet. It’s probably involved in some important function in the brain.

The reason prions are infectious is that they cause other proteins to misfold when they come into contact with them. The way proteins fold is *stupidly* complex and takes supercomputers to figure out. The important thing to know is that nothing in your body folds them, they fold themselves as they’re built. Every amino acid has its own shape with different charges sticking out one way or the other – like how water is a polar molecule. As the amino acids are bound together by the ribosomes building them, the charges attract and repel each other so that the protein twists and folds into its final shape.

*Most* of the time – as far as anyone can tell – the end shape is the most stable shape that protein can take. Prions happen because the normal shape is *not* the most stable shape. Consider a typical light switch. There is a spring inside so that if you try to leave it sitting in the middle, the spring will pull it to one side. In either the on or off position, the switch is *stable* and even though the spring is still in tension, the spring holds the light switch in that position. You have to push on it a fair bit to get it out of that position, but when you do it will snap into the other position.

A prion is kind of like that. Instead of one stable “position” or shape, the normal protein is more like a light switch and has a second stable shape. And, in fact, the wrong shape is *more* stable, meaning that it kind of already wants to snap out of the normal shape. It’s like a light switch where the spring is stronger on one side than the other, so if you make it just a little unstable – you take it just a little out of the position it’s in – it will prefer to snap into the more stable, stronger-spring direction.

So, when a prion comes into contact with a normal version of that protein its own wrong shape pushes on the protein enough to make unstable enough to change its shape, and the prion’s shape pushes on the unstable protein so that it will become another prion. Now, instead of having *one* protein that isn’t doing its job there are two, and both of them will change *other* proteins into even *more* prions. Two becomes four, then eight…after only a few generations there are far more prions than normal proteins, and the job they’re needed to do isn’t getting done.

Even *worse*, there is evidence that one reason your body evolved not to use the prion shape in the first place is that the prions can stack on top of each other kind of like Lego bricks. Instead of merely bumping into each other and then wandering off again, they can stick together to form big, long stacks. These proteins don’t just fail to work, these big stacks physically clog up the system, preventing unrelated proteins from doing *their* job, and blocking other vital resources from traveling through your brain.

The end result is that your brain starts falling apart, both metaphorically and literally. The general term for prion-caused diseases is *spongiform encephalitis*. *Encephalitis* means “brain disease” and *spongiform* means “sponge-like” – as in, your brain is full of holes, like a sponge.

Folding is, like, one of *the* main things about proteins. All proteins are made of the same few building blocks – putting them in a different order causes the protein to “fold” into a different shape, and the shape is what makes them different. If it folds differently, then it’s a different protein. (Shape isn’t the *only* factor – it does also matter which building blocks are at different spots in the shape)

Proteins fold wrongly all the time, but it’s very unusual that a wrongly folded protein causes other proteins to fold wrongly *and* can’t be unfolded or recycled automatically.