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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Local protein synthesis is essential for neuronal function.
• Dysregulation of this process is implicated in neurodegenerative diseases like ALS, but mechanisms are unclear.
• Spatial transcriptomics offers a novel approach to map subcellular RNA localization.

Purpose of the Study:

• To investigate the role of local protein synthesis in neuronal axons.
• To explore the impact of amyotrophic lateral sclerosis (ALS)-associated Fused in Sarcoma (FUS) mutations on axonal translation.
• To identify therapeutic targets for FUS-related neurotoxicity.

Main Methods:

• Spatial transcriptomics applied to mouse motor nerve axons and cell bodies.
• Multiplexed single-molecule spatial transcriptomics and immunofluorescence to confirm translation machinery localization.
• Analysis of RNA signatures and translation factor Eif5a in FUS mutant models.

Main Results:

• Protein translation is the most enriched biological process in mature axons.
• ALS-associated FUS mutations disrupt axonal RNA signatures and impair local translation machinery, specifically Eif5a hypusination.
• Axon-specific spermidine treatment restored Eif5a hypusination and ameliorated FUS-dependent neuronal defects.

Conclusions:

• Local protein synthesis is compartmentalized in axons and crucial for neuronal health.
• Impaired Eif5a hypusination in FUS-mutant axons contributes to neurodegeneration.
• Spermidine shows therapeutic potential for ALS by restoring axonal translation and reducing toxicity in FUS and TDP-43 models.