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

This is the authors' abstract. We don't add key points for this paper.

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. Piol et al. uncover that impaired eukaryotic initiation factor 5a (Eif5a) hypusination disrupts axonal translation and neuronal activity in fused in sarcoma-amyotrophic lateral sclerosis (FUS-ALS) by applying spatial transcriptomics in motor axons. In vitro and in vivo targeting Eif5a hypusination via spermidine supplementation improves ALS model phenotypes.