Zhejiang Provincial Key Laboratory of Pancreatic Disease, Department of Neurobiology, First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310020, China.
MOE Frontier Science, Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou, Zhejiang 310058, China. E-mail:
Zool Res. 2023 Mar 18;44(2):331-340. doi: 10.24272/j.issn.2095-8137.2022.356.
Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease, in which lower motoneurons lose control of skeletal muscles. Degeneration of neuromuscular junctions (NMJs) occurs at the initial stage of ALS. Dipeptide repeat proteins (DPRs) from G4C2 repeat-associated non-ATG (RAN) translation are known to cause C9orf72-associated ALS (C9-ALS). However, DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients, indicating that DPRs may exert cell non-autonomous effects, in addition to the known intracellular pathological mechanisms. Here, we report that poly-GA, the most abundant form of DPR in C9-ALS, is released from cells. Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission . The NMJ structure cannot be maintained, as evidenced by the fragmentation of postsynaptic acetylcholine receptor (AChR) clusters and distortion of presynaptic nerve terminals. Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling. Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS. Thus, targeting NMJs could be an early therapeutic intervention for C9-ALS.
肌萎缩侧索硬化症（ALS）是一种毁灭性的运动神经元疾病，其中较低的运动神经元失去对骨骼肌的控制。神经肌肉接头（NMJs）的退化发生在 ALS 的初始阶段。已知来自 G4C2 重复相关非 ATG（RAN）翻译的二肽重复蛋白（DPRs）会导致 C9orf72 相关 ALS（C9-ALS）。然而，DPR 包含负担与 C9-ALS 患者的神经退行性区域相关性较弱，表明 DPR 可能除了已知的细胞内病理机制外，还具有细胞非自主性效应。在这里，我们报告 C9-ALS 中最丰富的 DPR 形式聚 GA 从细胞中释放出来。聚 GA 蛋白在周围突触区域的局部给药会导致肌肉无力和神经肌肉传递受损。NMJ 结构无法维持，这表现为突触后乙酰胆碱受体（AChR）簇的碎片化和突触前神经末梢的扭曲。机制研究表明，细胞外聚 GA 会隔离可溶性 Agrin 配体并抑制 Agrin-MuSK 信号传导。我们的研究结果提供了一种新的细胞非自主性机制，即聚 GA 会损害 C9-ALS 中的 NMJ。因此，针对 NMJ 可能是 C9-ALS 的早期治疗干预措施。
