# Biomolecular condensates (liquid-liquid phase separation)

Biomolecular condensates are membraneless 'organelles' that form by liquid-liquid phase separation (LLPS). That is the spontaneous demixing of proteins and RNAs into a dense liquid droplet, like oil separating from water. The driving force is many weak, multi-point interactions. They happen among floppy protein regions (intrinsically disordered regions, or IDRs) and low-complexity sequences. That lets the droplets form and dissolve fast in response to signals. Key examples include stress granules (protein-RNA blobs that stash mRNA during stress), P-bodies, nucleoli, and Cajal bodies. Brangwynne et al. (Science, 2009) showed the principle. 'P granules' in a worm fuse and dissolve like liquid drops. That established LLPS as a general organizing principle. With age, this regulation breaks down. Droplets made by RNA-binding proteins TDP-43 and FUS slowly harden into amyloid-like fibers. This liquid-to-solid switch is central to ALS and frontotemporal dementia. Molliex et al. (Cell, 2015) showed this phase separation drives stress-granule formation. They also showed the crowded protein environment speeds the harmful fibrillization. Alberti and Hyman (2021) pulled the evidence together. As you age and proteostasis weakens (less chaperone activity, less autophagy), the safeguards that keep droplets liquid are lost. Drugs that target condensate fluidity are in preclinical study. None has reached approval.

## Sources

- Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C, Gharakhani J, et al.. (2009). Germline P Granules Are Liquid Droplets That Localize by Controlled Dissolution/Condensation. Science. https://doi.org/10.1126/science.1172046
- Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, et al.. (2015). Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization. Cell. https://doi.org/10.1016/j.cell.2015.09.015
- Alberti S, Hyman AA. (2021). Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-020-00326-6

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