The ALS-associated protein FUS forms liquid-like compartments in both in vivo and in vitro settings. These compartments are crucial for cellular functions such as DNA repair and stress response. However, these compartments can transition into an aberrant aggregated state over time, a process accelerated by disease-associated mutations. The study shows that FUS, containing a prion-like low-complexity domain, forms dynamic liquid compartments that are essential for its physiological role. These compartments carry a trade-off between functionality and the risk of aggregation. Aberrant phase transitions within these compartments are implicated in ALS and other age-related diseases. FUS forms liquid compartments in response to DNA damage and stress, and these compartments can convert into solid aggregates, especially when disease mutations are present. In vitro experiments demonstrate that FUS can phase separate into liquid droplets, which can transition into fibrous aggregates over time. Patient-derived mutations, such as G156E, accelerate this transition, leading to the formation of fibrous structures. These structures resemble the pathological aggregates seen in ALS patients. The study also shows that FUS compartments have liquid-like properties, including rapid internal rearrangement, spherical shapes, and the ability to fuse and relax into one droplet. These properties suggest that FUS compartments are dynamic and essential for cellular processes. However, under physiological conditions, FUS does not form solid-like aggregates but instead forms dynamic droplets that exhibit all the properties of a true liquid. The formation of FUS compartments is influenced by factors such as PAR (poly(ADP) ribose) polymerase activity, which is involved in DNA damage response. PAR polymers are required for the recruitment of FUS to DNA damage sites and for the prolonged presence of FUS in these compartments. In vitro experiments show that the presence of PAR enhances the formation of FUS droplets, while the absence of PAR inhibits this process. Patient-derived mutations, such as G156E, accelerate the conversion of FUS droplets into fibrous aggregates, which is consistent with the increased aggregation propensity of these mutations. The study also shows that the aggregation of FUS is concentration-dependent, and mutations that increase the cytosolic concentration of FUS can accelerate the formation of aggregates. The findings suggest that aberrant phase transitions in FUS compartments may be at the heart of ALS and other neurodegenerative diseases. The liquid-to-solid phase transition of FUS is accelerated by mutations that increase the aggregation propensity of the protein. These findings highlight the importance of maintaining the dynamic balance between liquid-like compartments and the risk of aggregation in cellular processes.The ALS-associated protein FUS forms liquid-like compartments in both in vivo and in vitro settings. These compartments are crucial for cellular functions such as DNA repair and stress response. However, these compartments can transition into an aberrant aggregated state over time, a process accelerated by disease-associated mutations. The study shows that FUS, containing a prion-like low-complexity domain, forms dynamic liquid compartments that are essential for its physiological role. These compartments carry a trade-off between functionality and the risk of aggregation. Aberrant phase transitions within these compartments are implicated in ALS and other age-related diseases. FUS forms liquid compartments in response to DNA damage and stress, and these compartments can convert into solid aggregates, especially when disease mutations are present. In vitro experiments demonstrate that FUS can phase separate into liquid droplets, which can transition into fibrous aggregates over time. Patient-derived mutations, such as G156E, accelerate this transition, leading to the formation of fibrous structures. These structures resemble the pathological aggregates seen in ALS patients. The study also shows that FUS compartments have liquid-like properties, including rapid internal rearrangement, spherical shapes, and the ability to fuse and relax into one droplet. These properties suggest that FUS compartments are dynamic and essential for cellular processes. However, under physiological conditions, FUS does not form solid-like aggregates but instead forms dynamic droplets that exhibit all the properties of a true liquid. The formation of FUS compartments is influenced by factors such as PAR (poly(ADP) ribose) polymerase activity, which is involved in DNA damage response. PAR polymers are required for the recruitment of FUS to DNA damage sites and for the prolonged presence of FUS in these compartments. In vitro experiments show that the presence of PAR enhances the formation of FUS droplets, while the absence of PAR inhibits this process. Patient-derived mutations, such as G156E, accelerate the conversion of FUS droplets into fibrous aggregates, which is consistent with the increased aggregation propensity of these mutations. The study also shows that the aggregation of FUS is concentration-dependent, and mutations that increase the cytosolic concentration of FUS can accelerate the formation of aggregates. The findings suggest that aberrant phase transitions in FUS compartments may be at the heart of ALS and other neurodegenerative diseases. The liquid-to-solid phase transition of FUS is accelerated by mutations that increase the aggregation propensity of the protein. These findings highlight the importance of maintaining the dynamic balance between liquid-like compartments and the risk of aggregation in cellular processes.