Local protein synthesis is vital for neuronal function and its dysregulation in neurodegenerative diseases remains poorly understood. One of the earliest events occurring in amyotrophic lateral sclerosis (ALS) is the denervation of the neuromuscular junctions (NMJs), suggesting local events as valuable therapeutic targets. Using spatial transcriptomics in the adult mouse motor nerve axons and cell bodies we mapped their transcriptional signature in healthy and mutant FUS animals for the identification of early molecular players in the maintenance of mature axons and their dysregulation in ALS. Among transcripts present in mature axons, protein translation emerges as the most highly enriched biological process, and the presence of the translational machinery was validated using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Mutations in the RNA-binding protein fused in sarcoma (FUS) linked to amyotrophic lateral sclerosis (ALS), which inhibit local protein synthesis, disrupt compartment-specific RNA profiles, including transcripts encoding components of the translation machinery. Notably, eukaryotic initiation factor 5A (Eif5a), a translation factor involved in initiation, elongation and termination, is locally compromised in axons expressing mutant FUS, showing reduced levels of its active hypusinated form. Axon-restricted treatment with the polyamine spermidine restores Eif5a hypusination and alleviates neuronal defects driven by mutant FUS, including impaired local protein synthesis. Finally, in vivo administration of spermidine decreases ALS-related toxicity in Drosophila models expressing mutant FUS and TDP-43, highlighting potential therapeutic relevance.