Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission

The amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for FUS (Fused in Sarcoma), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in C. elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons...肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）作为一种神经退行性疾病，已被证实与多种遗传损伤相关，其中包括编码肉瘤融合蛋白（Fused in Sarcoma, FUS）的基因发生突变——FUS是一类核定位的RNA/DNA结合蛋白。在秀丽隐杆线虫（C. elegans）中异位表达致病型FUS蛋白，会导致FUS在细胞质中出现定位异常与聚集，并引发运动能力受损。然而，突变型FUS破坏神经元健康与功能的具体机制仍未明确。本研究采用关联光镜电镜技术、电子断层扫描以及电生理学方法，探究了ALS相关FUS对运动神经元健康的影响。研究结果显示，异位表达野生型或ALS相关的人源FUS，会损伤神经肌肉接头处的突触囊泡锚定过程；ALS相关FUS可诱导产生一类大型、电子致密且充满丝状物的内体群体；电生理记录显示运动神经元的信号传递能力出现减弱……