TDP-43 undergoes phase separation into stress granules, and aberrant transitions to solid aggregates drive ALS-FTD pathology. Small molecules (including GRP75 modulators, nuclear export inhibitors, and RNA chaperones) have shown preclinical promise, but selectivity for pathological vs functional phase separation is unresolved.
TDP-43 undergoes liquid-liquid phase separation that becomes pathological. Small molecules targeting phase separation properties could be therapeutic but the design principles are undefined.