Here, we demonstrated that three different FTLD-related TDP-43 missense mutations are causative of massive death in yeast cells, but—similarly to WT and ALS-linked mutant TDP-43—the cytotoxicity can be efficiently counteracted by the co-expression of vectors encoding for human NCL, further confirming our previous results indicating NCL as a player able to greatly reduce the TDP-43-induced cell damage [32]. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.