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

Porebski, B.; Lafarga, V.; Hansel, C.; Haraldsson, M.; Saez-Mas, A.; Sanchez-Mollaeda, A.; Moragon, S.; Haggblad, M.; Lidemalm, L.; Rodrigo, S.; Carreras-Puigvert, J.; Ventoso, I.; Lafarga, M.; Huhn, D.; Fernandez-Capetillo, O.

2026-03-15 molecular biology
10.64898/2026.03.15.711847 bioRxiv
Show abstract

C9ORF72 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 the accumulation of orphan ribosomal proteins (RP). 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, a specialized form of autophagy 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 in ribosome biogenesis, which triggers a protective response to clear defective ribosomes. Accordingly, SALSa accumulates in nucleoli and perturbs the final steps of rRNA maturation. SALSa reduces DPR toxicity in differentiated neurons and 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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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.