Several studies have reported an interesting dichotomy in TDP-43, where the NTD regulates normal TDP-43 structure and function16,24,27 while also participating in driving TDP-43 aggregation in TDP-43 proteinopathies.15–17,19 TDP-43 forms physiological and reversible oligomers mediated by the NTD, and these physiological oligomers may serve as precursors for pathological and irreversible protein inclusions. Here, TARDBP is linked to proteostasis deficiencies.