Modulating liquid–liquid phase separation of FUS: mechanisms and strategies

Liquid-liquid phase separation (LLPS) of biomolecules inspires the construction of protocells and drives the formation of cellular membraneless organelles. The resulting biomolecular condensates featuring dynamic assembly, disassembly, and phase transition play significant roles in a series of biological processes, including RNA metabolism, DNA damage response, signal transduction and neurodegenerative disease. Intensive investigations have been conducted for understanding and manipulating intracellular phase-separated disease-related proteins (e.g., FUS, tau and TDP-43). Herein, we review current studies on the regulation strategies of intracellular LLPS focusing on FUS, which are categorized into physical stimuli, biochemical modulators, and protein structural modifications, with summarized molecular mechanisms. This review is expected to provide a sketch of the modulation of FUS LLPS with its pros and cons, and an outlook for the potential clinical treatments of neurodegenerative diseases.