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How does a protein come to be misfolded? Is it a random mutation that happens to be self-propagating? Is it different between alzheimers and other ones like mad cow?



Thermodynamics.

Certain proteins have a propensity to Misfold, this is driven by the folding conformations as well as by Heat Shock Proteins. The underlying genetics that drive amino acid sequence are the basis for this. In the best known prion disease, Mad Cow, one misfolded protein drives other similar proteins it runs into to induce the same conformation. Due to the thermodynamics of folding, it is now in a very stable structure and won’t revert to its original or desired biological structure, is difficult or impossible to clear, and will cause other proteins to fold in the same way.


So the first misfolded protein is just a random occurrence?

With mad cow, will uninfected cow populations spontaneously develop mad cow on their own? Or was the first mad cow protein a rare misfortune not likely to happen again? Or did the first mad cow protein come from something other than a cow?


Look up the sheep prion disease scrapie. It’s been around a lot longer than mad cow (1700s) and likely continues to arise spontaneously.

The protein structure needs to have a mutation which gives it a propensity to occasionally misfold. That creates a chain reaction. If this happens at a low enough rate then the underlying protein may become widely distributed in the population, and then it may only take a chance mutation or misfold to cause the cascade

The reality is we don’t know what the prime mover in any of these conditions are. Likely some combination of random occurance and possibly some other mechanism as well. For example, CJD comes from mad cow - so mad cow is transmissible, but scrapie seems to both arise spontaneously in flocks and be transmissible between sheep


I have no idea what the mechanisms affecting protein folding are in this context, but if you are interested in learning more about how proteins fold and perhaps helping researchers fold interesting new ones, check out FoldIt (a protein folding citizen science project): https://fold.it/portal/

It was featured in Werner Herzog's Lo and Behold and I had the privilege of taking a class taught by a professor involved in its development. The community there can do a little bit to restore your faith in humanity and technology.


This still exists? I'll have to check it out again sometime...


This is all preliminary, so nobody knows for sure about Alzheimers, but assuming it was, then it would likely be a different protein. (IOW a different linear chain of amino acids, that folded in a non-standard way.)




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