Although TDP-43 mutations are rare, TDP-43 proteinopathies, characterized by cytoplasmic mislocalization, aggregation, and cleavage of TDP-43 accompanied by its nuclear clearance, are found in the affected regions of the CNS in up to 97% of all ALS cases, except for those fALS caused by SOD1 or FUS mutations (Neumann et al., 2006; Mackenzie et al., 2010), suggesting a broader involvement for TDP-43 dysregulation in ALS. Here, TARDBP is linked to proteostasis deficiencies.