Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation.

Inhibition of nuclear export reduces pathogenic TDP-43 aggregation and phospho-TDP-43 accumulation in ALS models, highlighting nuclear transport as a key modulator.

• Why it matters: TDP-43 aggregation is a hallmark of neurodegenerative diseases like ALS, but the cellular mechanisms controlling its phase transition are not well understood, limiting therapeutic development.
• What they did: Researchers used chemical and genome-wide genetic screens to identify cellular processes, including RNA splicing, translation, proteostasis, and nuclear export, that influence TDP-43 phase behavior, and developed a semi-permeabilized cell system to study phase transitions.
• The result: Findings show nuclear export inhibition promotes RNA-dependent liquid-liquid phase separation of TDP-43, reducing its aggregation and pathogenic forms, providing a framework for targeting nuclear transport in neurodegeneration.