PDF(Pubmed)
Abstract：
Aberrant condensation and localization of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Changes in RBP function are commonly associated with changes in axonal cytoskeletal organization and branching in neurodevelopmental disorders. Here, we asked whether branching defects also occur in vivo in a model of FUS-associated disease. We use two reported Xenopus models of ALS/FTD (of either sex), the ALS-associated mutant FUS(P525L) and a mimic of hypomethylated FUS, FUS(16R). Both mutants strongly reduced axonal complexity in vivo. We also observed an axon looping defect for FUS(P525L) in the target area, which presumably arises due to errors in stop cue signaling. To assess whether the loss of axon complexity also had a cue-independent component, we assessed axonal cytoskeletal integrity in vitro. Using a novel combination of fluorescence and atomic force microscopy, we found that mutant FUS reduced actin density in the growth cone, altering its mechanical properties. Therefore, FUS mutants may induce defects during early axonal development.
摘要：
在肉瘤（FUS）中融合的RNA结合蛋白（RBP）的异常浓缩和定位发生在肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）的变体中。RBP功能的变化通常与神经发育障碍中轴突细胞骨架组织和分支的变化有关。这里,我们询问在FUS相关疾病模型中体内是否也存在分支缺陷.我们使用了两种报道的ALS/FTD（两种性别）的非洲爪狼模型，ALS相关突变体FUS（P525L）和低甲基化FUS的模拟物，FUS（16R）。两种突变体在体内都大大降低了轴突复杂性。我们还在目标区域观察到FUS（P525L）轴突成环缺陷，这可能是由于停止提示信号的错误引起的。为了评估轴突复杂性的丧失是否也具有与线索无关的成分，我们使用荧光和原子力显微镜的新型组合在体外评估轴突细胞骨架的完整性，我们发现突变体FUS降低了生长锥中的肌动蛋白密度，改变其机械性能。因此,FUS突变体可能在早期轴突发育过程中诱导缺陷。意义陈述这项研究表明，ALS/FTD（肌萎缩侧索硬化症/额颞叶痴呆）相关RNA结合蛋白的突变融合在肉瘤（FUS）中可以导致轴突发育的变化。这些变化在轴突延伸过程中在细胞骨架组织中轴突自主发生，在轴突分支过程中与上下文相关。这表明症状前，在家族性疾病变异型中可能发生轴突组织的发育变化.
