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A chemical inducer of ribophagy limits the toxicity of ALS-related arginine-rich peptides

GSE324761 Homo sapiens Expression profiling by high throughput sequencing 4 samples Submitted 2026/03/23 Platform GPL21697
Summary
9ORF72 intronic repeat expansions are the most frequent mutation found in Amyotrophic Lateral Sclerosis (ALS), producing toxic arginine-rich dipeptides (DPR) that disrupt RNA metabolism and trigger orphan ribosomal protein (RP) accumulation. Through a large phenotypic chemical screen, we identified “SALSa”, a novel compound that mitigates DPR toxicity. Mechanistically, SALSa acts as a chemical inducer of ribophagy that promotes RP clearance. Interestingly, this effect is unrelated to mTOR inhibition, the main regulator of autophagy. In contrast, this is due to an effect of the drug on ribosome biogenesis, which triggers a protective response to clear defective ribosomes. Accordingly, SALSa accumulates at nucleoli and perturbs the final steps of rRNA maturation. Finally, SALSa significantly extends lifespan in a Drosophila melanogaster model of C9ORF72 ALS. These findings suggest that stimulating ribophagy could be beneficial for pathologies associated to dysfunctional ribosome biogenesis, including C9ORF72 ALS.
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Also filed as BioProject PRJNA1436989 and SRA study SRP683392. Searching any of these in the dataset finder brings you back here.

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