ALS/FTLD-Linked Mutations in FUS Glycine Residues Cause Accelerated Gelation and Reduced Interactions with Wild-Type FUS.

The RNA-binding protein Fused in sarcoma (FUS) can form pathogenic inclusions in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Over 70 mutations in Fus are linked to ALS/FTLD. In patients, all Fus mutations are heterozygous, indicating that the mutant drives disease progression despite the presence of wild-type FUS. Here, we demonstrate that ALS/FTLD-linked FUS mutations in glycine (G) strikingly drive formation of droplets that do not readily interact with wild-type FUS whereas arginine (R) mutants form mixed condensates with wild-type FUS. Remarkably, interactions between wild-type and G mutants are disfavored at the earliest stages of FUS nucleation. In contrast, R mutants physically interact with the wild-type FUS such that wild-type FUS recovers the mutant defects by reducing droplet size and increasing dynamic interactions with RNA. This result suggests disparate molecular mechanisms underlying ALS/FTLD pathogenesis and differing recovery potential depending on the type of mutation. FUS is an RNA binding protein with over seventy mutations linked to the incurable neurodegenerative diseases, ALS/FTLD. Rhine et al demonstrates that FUS mutations in glycine do not associate with the wildtype at all levels while the mutations in arginine interacts with wildtype FUS and thereby recover the mutant defect.

RNA结合蛋白肉瘤融合蛋白（FUS）在肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTLD）等神经退行性疾病中可形成致病性包涵体。Fus的70多种突变与ALS/FTLD相关。在患者中，所有Fus突变都是杂合的，这表明尽管存在野生型FUS，突变体仍会推动疾病进展。在此，我们证明与ALS/FTLD相关的甘氨酸（G）中的FUS突变显著促使液滴形成，这些液滴不易与野生型FUS相互作用，而精氨酸（R）突变体则与野生型FUS形成混合凝聚物。值得注意的是，在FUS成核的最早阶段，野生型与G突变体之间的相互作用就不被看好。相比之下，R突变体与野生型FUS发生物理相互作用，使得野生型FUS通过减小液滴大小以及增加与RNA的动态相互作用来弥补突变缺陷。这一结果表明ALS/FTLD发病机制存在不同的分子机制，并且根据突变类型的不同恢复潜力也不同。 FUS是一种RNA结合蛋白，有70多种突变与无法治愈的神经退行性疾病ALS/FTLD相关。莱茵等人证明甘氨酸中的FUS突变在所有层面都不与野生型相关联，而精氨酸中的突变则与野生型FUS相互作用，从而弥补突变缺陷。