比利时鲁汶大学单细胞组学研究所Sandrine Da Cruz小组宣布他们的研究开发出了轴突Eif5a蛋白的羟腐胺化修饰调控局部蛋白质合成并缓解FUS-ALS相关缺陷。2025年12月22日出版的《自然—神经科学》发表了这项成果。

在这里，该课题组人员将空间转录组学应用于成人无主题运动神经轴突和细胞体，以实现亚细胞定位。在成熟轴突中发现的转录本中，最丰富的生物过程是蛋白质翻译，翻译机制的定位通过多路单分子空间转录组学与免疫荧光相结合得到证实。肌萎缩性侧索硬化症（ALS）与肉瘤（FUS）中RNA结合蛋白相关的突变抑制了局部翻译，破坏了室特异性RNA特征，包括翻译机制的组成部分。

特别是，真核起始因子5a (Eif5a)，一种参与延伸和终止的翻译因子，被发现在突变的FUS轴突中局部受损，其活性低铁化形式水平降低。多胺亚精胺轴突特异性治疗可恢复Eif5a低钠化，改善突变型FUS依赖性神经元缺陷，包括抑制局部蛋白质合成。最后，体内亚精胺治疗降低了突变FUS和TDP-43果蝇模型中ALS相关的毒性，这可能对治疗发展有影响。

据介绍，局部蛋白质合成对神经元功能至关重要，但其在神经退行性疾病中的失调仍不清楚。

附：英文原文

Title: Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS

Author: Piol, Diana, Khalil, Bilal, Robberechts, Tessa, Killian, Theo, Georgopoulou, Maria, Partel, Gabriele, Wouters, David, Hecker, Nikolai, Tziortzouda, Paraskevi, Verresen, Yana, Corthout, Nikky, Kint, Sam, Vandereyken, Katy, Van Damme, Philip, Voet, Thierry, Davie, Kristofer, Poovathingal, Suresh, Van Den Bosch, Ludo, Aerts, Stein, Sifrim, Alejandro, Da Cruz, Sandrine

Issue&Volume: 2025-12-22

Abstract: Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.

DOI: 10.1038/s41593-025-02101-2

Source: https://www.nature.com/articles/s41593-025-02101-2