We recently had a very interesting debate around the mechanisms of toxicity in neurodegenerative diseases (NDDs) and whether it is mainly a gain-of-function (GOF) or loss-of-function (LOF) toxicity due to amyloid aggregation. Before the debate, the inspiring patient advocate Marina Noordegraaf ( @Sparks4PD ) asked me if the GOF and LOF proponents could switch sides during the debate and try to defend the other point of view. I apologized to her saying that it would be very difficult for me to defend GOF since the most common GOF defenses are counterfactual. Here I will list some of the common GOF defenses that we usually get whenever we discuss LOF in papers, reviews, seminars, or on Twitter. 1. K nock out/down a nimals of the amyloidogenic proteins show no phenotype, thus not supporting LOF This is just not true . While there is never going to be a perfect animal model that accurately reflects all aspects of the human pathology (and this is true...
