Why LOF was lost?
Why LOF was lost? When a protein aggregates, two things happen, one is certain and the other is uncertain. - The certain consequence is that the protein loses its function, because any protein needs its native conformation and solubility to function → loss-of-function (LOF) - The uncertain consequence is that the resulting aggregates become particularly more toxic → gain-of-function (GOF) While the two mirror-image possibilities are scientifically valid, the majority of the field studying amyloids, especially within neurodegenerative diseases, chose to focus on the uncertain consequence (GOF) and almost completely ignore the certain one (LOF). A friend of mine asked me why? Why something as obvious as LOF became almost unthinkable and is only mentioned shyly as a heretic belief on the outskirts of the literature? Here, I will try to discuss the historical factors that I think contributed to this huge asymmetry in amyloid science, and how this uni...