Fused in sarcoma (FUS) is a DNA/RNA binding protein that is involved in RNA metabolism and DNA repair. Numerous reports have demonstrated by pathological and genetic analysis that FUS is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and polyglutamine diseases. Traditionally, the fibrillar aggregation of FUS was considered to be the cause of those diseases, especially via its prion-like domains (PrLDs), which are rich in glutamine and asparagine residues. Lately, a nonfibrillar self-assembling phenomenon, liquid–liquid phase separation (LLPS), was observed in FUS, and studies of its functions, mechanism, and mutual transformation with pathogenic amyloid have been emerging. This review summarizes recent studies on FUS self-assembling, including both aggregation and LLPS as well as their relationship with the pathology of ALS, FTLD, and other neurodegenerative diseases.

A repetitive basic-acidic motif in U1-70K is critical for its phase separation and aggregation.

Liquid-liquid phase separation (LLPS) plays important roles in various cellular processes, facilitating membrane-less organelles construction, chromatin condensation, signal transduction on inner membrane and many other processes. Current perception is that LLPS relies on weak multivalent interactions and crowded environments intracellularly. In this study, we demonstrate that heparan sulfate can serve as a platform to induce the phase separation of basic fibroblast growth factor on cell surface. The phase separation model provides an alternative mechanism how bFGF is enriched to its receptors, therefore triggering the signaling transduction. The research provides insights on the mechanism how growth factors can be recruited to cell surface by heparan sulfate and execute their functions, extending people’s view on phase separation from intracellular to extracellular proteins at cellular level.

Tobacco use disorder is the leading cause of disease and preventable death worldwide, but current medications that are based on pharmacodynamics have low efficacy. Novel pharmacokinetic approaches to prevent nicotine from reaching the brain have been tested using vaccines, but these efforts have failed because antibody affinity and concentration are not sufficient to completely prevent nicotine from reaching the brain. We provide preclinical evidence of the efficacy of an enzymatic approach to reverse nicotine dependence, reduce compulsive-like nicotine intake, and prevent relapse in rats with a history of nicotine dependence. Chronic administration of NicA2-J1, an engineered nicotine-degrading enzyme that was originally isolated from Pseudomonas putida S16, completely prevented nicotine from reaching the brain and reversed somatic signs of withdrawal, hyperalgesia, and irritability-like behavior in nicotine-dependent rats with a history of escalation of nicotine self-administration. NicA2-J1 also decreased compulsive-like nicotine intake, reflected by responding despite the adverse consequences of contingent footshocks, and prevented nicotine- and stress (yohimbine)–induced relapse. These results demonstrate the efficacy of enzymatic therapy in treating nicotine addiction in advanced animal models and provide a strong foundation for the development of biological therapies for smoking cessation in humans.