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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324761 | GEO | 2026/03/23

REPOSITORIES: GEO

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Project description:Amyotrophic lateral sclerosis (ALS) is a deleterious neurodegenerative disease without effective treatment options. Recent studies have indicated the involvement of the dysregulation of RNA metabolism in the pathogenesis of ALS. Among the various RNA regulatory machineries, nonsense-mediated mRNA decay (NMD) is a stress responsive cellular surveillance system that degrades selected mRNA substrates to prevent the translation of defective or harmful proteins. Whether this pathway is affected in neurodegenerative diseases is unclear. Here we report that the NMD pathway is inhibited in ALS patients with C9orf72 hexanucleotide repeat expansion (HRE), the most common cause of familial ALS. Bioinformatic analysis of multiple transcriptome profiles revealed significant overlap of upregulated genes in NMD-defective cells with those in the brain tissues, micro-dissected motor neurons, or induced pluripotent stem cell-derived motor neurons from ALS patients carrying C9orf72 HRE, suggesting the suppression of NMD pathway in these patients. In contrast, there are few overlapping upregulated genes in brain tissues from sporadic ALS patients with those in NMD-defective cells. Using Drosophila models expressing various C9orf72 HRE products, we have validated the suppression of the NMD pathway by C9orf72 HRE and identified arginine-rich dipeptide repeats (DPRs) generated from HRE as the main culprits of NMD inhibition. Furthermore, in human SH-SY5Y neuroblastoma cells and in mouse brains, expression of arginine-rich DPRs was sufficient to cause NMD inhibition. Remarkably, expression of UPF1, a core gene in the NMD pathway, efficiently blocked neurotoxicity caused by arginine-rich DPRs in both cellular and Drosophila models. Although not as effective as UPF1, expression of another NMD gene UPF2 also ameliorated the degenerative phenotypes in DPR-expressing flies, indicating neuroprotection by genetically reactivating the NMD pathway. Finally, after validating Tranilast as an NMD-activating drug, we demonstrated its therapeutic potential in cellular and Drosophila models of C9orf72 DPR neurotoxicity. Therefore, our study has revealed the suppression of NMD in C9orf72 ALS and has suggested that the restoration of the NMD pathway by Tranilast, an asthma drug with solid safety record, could be a promising therapeutic strategy for ALS.

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

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