Altogether these Drosophila results show that, while retaining sufficient activity in neuronal context to rescue the lethal neurodevelopmental null phenotype, TDP-43p.Trp385IlefsTer10 loses its toxic gain-of-function properties upon overexpression in WT TBPH backgrounds and thus behaves very differently from full-length WT or ALS-mutant TDP-43. Here, TARDBP is linked to amyotrophic lateral sclerosis.