ArticleThe EMBO journal2020
The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS.
Article in The EMBO journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- RAN Translation-Coupled Decay of theInternational journal of molecular sciences · 2026Article
- Review
- High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.Nucleic acids research · 2025Article
- PABPC1 mediates degradation ofiScience · 2024Article
- dCas13-mediated translational repression for accurate gene silencing in mammalian cells.Nature communications · 2024Article
- Review
- RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due toJMA journal · 2023Review
- Intracellular and intercellular transport of RNA organelles in CXG repeat disorders: The strength of weak ties.Frontiers in molecular biosciences · 2022Review
- The Interplay Between Autophagy and RNA Homeostasis: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.Frontiers in cell and developmental biology · 2022Review
- Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function.International journal of molecular sciences · 2021Review
- C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels.Autophagy · 2021Review
- Exosome microRNAs in Amyotrophic Lateral Sclerosis: A Pilot Study.Biomolecules · 2021Article
- The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS.The EMBO journal · 2020Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of defective RNA. Here, we uncover the RNA exosome as a major degradation complex for pathogenic C9orf72-derived repeat RNA. Knockdown of EXOSC10, the catalytic subunit of the complex, enhanced repeat RNA and DPR protein expression levels. RNA degradation assays confirmed that EXOSC10 can degrade both sense and antisense repeats. Furthermore, EXOSC10 reduction increased RNA foci and repeat transcripts in patient-derived cells. Cells expressing toxic poly-GR or poly-PR proteins accumulate a subset of small nucleolar RNA precursors, which are physiological substrates of EXOSC10, as well as excessive repeat RNA, indicating that arginine-rich DPR proteins impair the intrinsic activity of EXOSC10. Collectively, arginine-rich DPR-mediated impairment of EXOSC10 and the RNA exosome complex compromises repeat RNA metabolism and may thus exacerbate C9orf72-FTLD/ALS pathologies in a vicious cycle.
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Registered trials
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