It’s quite remarkable that after so many years of studying prions we still don’t have a good understanding of their pathogenesis – how do they make normal cellular proteins turn evil? This interesting article suggests that it’s not the end stage amyloid deposits that we should be focussing on, but the toxicity (or otherwise) of the intermediate oligomers which generate the fibres and plaques.
Good Amyloid, Bad Amyloid—What’s the Difference? (2016) PLoS Biol 14(1): e1002362. doi:10.1371/journal.pbio.1002362
Amyloids have had some bad press. From Alzheimer to Parkinson, Huntington to Creutzfeldt-Jakob, amyloids are best known for their role in causing some very serious human diseases. The usual story is that the structure of a perfectly respectable, neatly folded (and usually soluble) protein is disrupted in some way, making it refold into a new “cross-beta” structure that predisposes multiple copies of that protein to tile together into a massive insoluble fibrous deposit. The trigger may be a mutation, an unusual cleavage pattern, a post-translational modification, or even (in the case of a class of amyloids called prions) infection by a ready-formed amyloid, but the end point tends to be the same – insoluble protein, cognitive problems, and eventual neurodegeneration.
Research has understandably been focused on the pathogenic amyloids that are involved in human neurological diseases, but several points have recently become clear. The first is that despite their suspicious presence at the scene of the crime, the insoluble deposits of amyloid may not themselves be the culprits and that instead it’s the smaller “oligomeric” assemblages or even the monomers of amyloidogenic protein (en route to fiber formation) that may cause the real damage. And the second is that not all amyloids are bad – some are biologically useful and have been selected for their beneficial function during evolutionary history.