Related Experiment Video
Updated: Aug 14, 2026
10:49
Measuring RAN Peptide Toxicity in C. elegans
Published on: April 30, 2020
RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat
You Wu1,2, Li Li1,2, Jing Tian1,2
1Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
International Journal of Molecular Sciences
|August 13, 2026
Summary
The RNA exosome, particularly EXOSC3, degrades toxic repeat-associated non-AUG (RAN) translation mRNA. This process suppresses neurotoxic dipeptide-repeat protein production, offering therapeutic insights for C9-ALS/FTD.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- The RNA exosome regulates mRNA processing and decay.
- Repeat-associated non-AUG (RAN) translation of C9orf72 expansions produces neurotoxic proteins implicated in C9-ALS/FTD.
- Mechanisms of C9orf72 mRNA surveillance and decay during RAN translation are not fully understood.
Purpose of the Study:
- To investigate the role of the RNA exosome in regulating RAN translation and C9orf72 mRNA decay.
- To determine if EXOSC3 influences RAN translation-coupled mRNA decay and DPR protein production.
- To explore the therapeutic potential of targeting the RNA exosome in C9-ALS/FTD.
Main Methods:
- Investigated the interaction between the RNA exosome and translating ribosomes on C9orf72 mRNA.
- Assessed the impact of EXOSC3 overexpression and knockdown on C9-HRE mRNA decay and DPR protein synthesis.
- Utilized induced pluripotent stem cell (iPSC)-derived neurons to model C9-ALS/FTD pathogenesis.
Main Results:
- RAN translation of C9orf72 mRNA triggers its rapid decay via the RNA exosome.
- EXOSC3 promotes RAN translation-coupled mRNA decay and reduces DPR protein production.
- Reduced EXOSC3 levels impair C9-HRE mRNA decay in a translation-dependent manner in neurons.
Conclusions:
- The RNA exosome, especially EXOSC3, plays a crucial role in surveilling and degrading C9orf72 mRNA during RAN translation.
- Targeting EXOSC3 may offer a therapeutic strategy to mitigate neurotoxicity in C9-ALS/FTD.
- This study provides insights into RAN translation regulation and potential treatments for related neurological disorders.
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