Biomolecular condensates (liquid-liquid phase separation)

Biomolecular condensates are membraneless organelles formed through liquid-liquid phase separation (LLPS) — the spontaneous demixing of proteins and RNAs into a dense liquid phase. The driving force is multivalent, low-affinity interactions among intrinsically disordered regions (IDRs) and low-complexity sequence domains (LCDs), enabling rapid condensation and dissolution in response to cellular signals. Key examples include stress granules (RNA–protein assemblies that sequester mRNAs during acute stress), P-bodies, nucleoli, and Cajal bodies. Brangwynne et al. (Science, 2009) showed that P granules in C. elegans fuse and dissolve like liquid droplets, establishing LLPS as a general organizing principle. During aging, condensate regulation deteriorates: condensates formed by RNA-binding proteins TDP-43 and FUS progressively harden into amyloid-like fibrillar aggregates — a liquid-to-solid transition central to ALS and frontotemporal dementia. Molliex et al. (Cell, 2015) demonstrated that LCD-driven phase separation drives stress granule condensation and that the protein-dense environment markedly accelerates pathological fibrillization. Alberti and Hyman (Nature Reviews Molecular Cell Biology, 2021) synthesized evidence that age-associated decline in proteostasis — reduced chaperone activity and autophagy flux — removes safeguards that normally prevent condensates from transitioning to irreversible solid states. Therapeutic strategies targeting condensate fluidity are under preclinical investigation; no LLPS-directed agent has reached clinical approval.