12 January 2026

Building proteins

Motor neurons depend on local protein production within their axons to support their long-distance connections to muscles. Using advanced spatial transcriptomics, scientists at the VIB–KU Leuven Center for Brain & Disease Research analyzed gene expression separately in neuron cell bodies and axons in adult mice. They found that axons contain unexpectedly high levels of the molecular machinery needed to make proteins.

In ALS models carrying disease-causing mutations in the RNA-binding protein FUS, this local protein production system was severely disrupted. The researchers traced the problem to Eif5a, a protein required for translation that must undergo a chemical modification called hypusination to function properly. In mutant neurons, the active form of Eif5a was specifically lost from axons, leading to reduced local protein synthesis.

A potential therapeutic role for spermidine

“We showed that local translation depends on the protein levels of Dohh, an enzyme essential for Eif5a hypusination,” says Dr. Diana Piol (VIB-KU Leuven, now at the University of Padova), first author of the study, “When we supplied axons with spermidine, a naturally occurring molecule needed for this modification, they were able to restore Eif5a activity. In turn, this improved local protein production, strengthened axonal structure, and enhanced neuronal activity.”

“These defects in protein production start locally in axons, long before the neurons themselves degenerate,” says senior author Prof. Sandrine Da Cruz (VIB–KU Leuven). “By restoring protein synthesis in axons, we were able to reduce disease-related damage in several ALS models. This discovery was enabled by the pioneering use of spatial transcriptomics to map gene expression within neuronal subcellular compartments, highlighting the critical role of distal axon homeostasis as a promising therapeutic target.”

Spermidine treatment also reduced toxicity in fruit fly models of ALS linked to both FUS and TDP-43, suggesting that this pathway may be relevant across multiple forms of the disease.

Although these findings do not yet lead directly to a treatment, they identify Eif5a hypusination as a promising therapeutic target and demonstrate how spatial analysis can reveal early, compartment-specific mechanisms in neurodegenerative disease.

Transversal section of adult spinal cord subjected to immunofluorescence combined with multiple single molecule FISH technology, with each dot indicating an individual mRNA target.

Publication

Piol D. et al. Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS. Nature Neuroscience, 2025

source: VIB