Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases.

Microtubules are polymeric protein structures and components of the cytoskeleton. Their dynamic polymerization is important for diverse cellular functions. The centrosome is the classical site of microtubule nucleation and is thought to be essential for axon growth and neuronal differentiation--processes that require microtubule assembly. We found that the centrosome loses its function as a microtubule organizing center during development of rodent hippocampal neurons. Axons still extended and regenerated through acentrosomal microtubule nucleation, and axons continued to grow after laser ablation of the centrosome in early neuronal development. Thus, decentralized microtubule assembly enables axon extension and regeneration, and, after axon initiation, acentrosomal microtubule nucleation arranges the cytoskeleton, which is the source of the sophisticated morphology of neurons.

Meiotic nuclear oscillations in the fission yeast Schizosaccharomyces pombe are crucial for proper chromosome pairing and recombination. We report a mechanism of these oscillations on the basis of collective behavior of dynein motors linking the cell cortex and dynamic microtubules that extend from the spindle pole body in opposite directions. By combining quantitative live cell imaging and laser ablation with a theoretical description, we show that dynein dynamically redistributes in the cell in response to load forces, resulting in more dynein attached to the leading than to the trailing microtubules. The redistribution of motors introduces an asymmetry of motor forces pulling in opposite directions, leading to the generation of oscillations. Our work provides the first direct in vivo observation of self-organized dynamic dynein distributions, which, owing to the intrinsic motor properties, generate regular large-scale movements in the cell.

No abstract