Whatever the pathogenic relevance of TDP-43 aggregation, identifying modifiers of TDP-43 toxicity and understanding the cell pathways altered by TDP-43 cytosolic mislocalization and its accumulation into protein condensates could unveil novel therapeutic strategies for TDP43-related proteinopathies, such as ALS and FTD. The gene discussed is TARDBP; the disease is proteostasis deficiencies.