While the origin and initiating cause of cytosolic TDP-43 accumulation remains enigmatic, recent studies have identified nucleocytoplasmic transport deficits as a key pathogenic mechanism involved in ALS and FTD, especially in C9ALS/FTD (Boeynaems et al., 2016a,b; Kim and Taylor, 2017; Hutten and Dormann, 2020). This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.