Mechanistic studies with ALS and FTD cell-based models indicate that disease-promoted cytoplasmic accumulations of TDP-43 can lead to the formation of TDP-43 aggregates that subsequently cause nuclear TDP-43 depletion and induce neuronal cell death (Walker et al., 2015; Gasset-Rosa et al., 2019; Tziortzouda et al., 2021). This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.