Science https://doi.org/10.1126/science.aar7366 (2018)
Aberrant aggregation of normally soluble proteins into insoluble amyloid is involved in the onset and the progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In the neurons of ALS patients, aggregation of prion-like RNA-binding proteins (RBPs) usually occurs in the cytoplasm rather than the nucleus. To investigate what prevents prion-like RBPs from forming solid-like aggregates in the nucleus, Maharana et al. used in vitro phase-separation assays and fluorescence correlation spectroscopy to show that RNA blocks the liquid–solid phase transition of prion-like RBPs, which is a prerequisite of aggregation. In living cells, assemblies of prion-like RBPs are observed by reducing the concentration of nuclear RNAs, by increasing intranuclear protein expression, or by impairing the RNA-binding ability of proteins. Photobleaching experiments showed that RNA kept condensates formed by prion-like RBPs in a dynamic state and prevented the formation of solid pathological assemblies. Overall, the findings suggest that nuclear RNA buffers the phase separation behavior of prion-like RBPs, provide insight into the chemical characteristics of this type of protein, and deepen the understanding of the pathological cause of prion-like RBP-related neurodegenerative diseases.