Nuclear export governs TDP-43 phase transitions and cytoplasmic aggregation

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like, nuclear assemblies whose phase transitions are linked to protein aggregation and neurodegeneration. The mechanisms that determine whether these assemblies remain dynamic or convert into solid states are poorly defined. Here we combined chemical and genome-wide genetic screenings to identify cellular processes influencing the phase behavior of an RNA-binding defective TDP-43 mutant associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While the screens identified multiple cellular processes--including RNA splicing, translation, and proteostasis--as modulators of TDP-43 phase states, our analyses underscore nuclear transport as a critical determinant of liquid-to-solid transitions. Inhibition of nuclear export prevents cytoplasmic accumulation of immobile TDP-43 assemblies, whereas enhanced export promotes irreversible, solid TDP-43 structures. We validated this mechanism in a brain organoid model of ALS, showing nuclear retention limits pathogenic aggregation and its associated defects. These findings establish nuclear export as a key regulator of TDP-43 phase transitions and define a mechanistic link between altered phase dynamics and neurodegeneration.