A closer look at how local protein production is altered in ALS

The functioning of neurons, cells that transmit information in the nervous system, heavily relies on the production of proteins. Proteins are synthesized both inside cells (i.e., in the soma) and locally along axons, projections via which signals are transmitted to other cells.

The local synthesis of proteins allows axons to rapidly respond to changes, grow and repair themselves, which in turn allows the formation of new connections in the brain associated with learning and memory. Past studies have linked disruptions in the local production of proteins to some neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

ALS is characterized by the progressive degradation of motor neurons, nerve cells that support voluntary muscle movements. Researchers at Leuven Brain Institute and KU Leuven in Belgium gathered new valuable insight into the contribution of local protein synthesis to this severe neurodegenerative disease, which they published in Nature Neuroscience.

Studying neurons that carry ALS-linked FUS mutations

To explore the link between protein synthesis in axons and ALS, the team analyzed mouse motor neurons using a technique known as spatial transcriptomics. Spatial transcriptomics allows neuroscientists to map gene expression directly within sections of tissue, shedding new light on how specific cell types and their locations support specific biological functions.

“Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined,” Diana Piol, Bilal Khalil and their colleagues wrote in their paper. “We applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping.”

Using spatial transcriptomics, Piol, Khalil and their colleagues identified RNA transcripts that were richer in axons or in cell somas. They then used another technique called immunofluorescence to visualize proteins in the mouse axons and cells, detecting RNA that support the synthesis of proteins. In their analyses, the team focused on mutations in a specific protein, called FUS (fused in sarcoma), which binds to RNA molecules and regulates the stability, transport and translation of RNA.

“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,” wrote the authors.

“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.”

Guiding the development of future ALS therapies

Piol, Khalil and their colleagues found evidence suggesting that proteins are partly synthesized inside axons, but this local production of proteins is disrupted when neurons carry mutations in the FUS gene. These FUS mutations lead to the reduced production of proteins in places where they are most needed, which was previously found to be associated with ALS.

As part of their study, the researchers also tried to restore local protein synthesis in fruit fly models of ALS, using a naturally occurring molecule called spermidine. They found that treating the mice with this molecule restored protein translation in axons, reducing damage to neurons.

“Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis,” wrote Piol, Khalil and their colleagues. “Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.”

Future studies could try to replicate these recent findings in additional experiments with other animal models of ALS, including mouse models. Eventually, if it is validated in humans, the insight gathered by this research team could inform the development of new therapeutic strategies that mitigate neurodegeneration by repristinating local protein synthesis processes.

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