RNA-binding proteins (RBPs) with prion-like domains (PrLDs) phase transition to functional liquids, which can mature into aberrant hydrogels composed of pathological fibrils that underpin fatal neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several nuclear RBPs with PrLDs including TDP-43, FUS, hnRNPA1, and hnRNPA2 mislocalize to cytoplasmic inclusions in ALS and FTD and mutations in their PrLDs can accelerate fibrillization and cause disease. Here, I will discuss our latest endeavors to uncover and engineer therapeutic protein disaggregases to reverse these aberrant phase transitions and restore functional RBPs to the nucleus to counter ALS and FTD disease phenotypes.