ALS and FTLD-TDP are characterized by a combination of loss-of-function (LOF), originating from the impoverishment of functional TDP-43 in the nucleus, and a gain-of-function (GOF), resulting from the formation of cytoplasmic TDP-43 assemblies that act as saboteurs with consequent dysfunction of cellular activities [12–16]. Here, TARDBP is linked to amyotrophic lateral sclerosis.