Related Experiment Video
Updated: Jul 23, 2025
10:49
Measuring RAN Peptide Toxicity in C. elegans
Published on: April 30, 2020
6.7K
FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked
Yuzo Fujino1,2, Morio Ueyama1,3,4, Taro Ishiguro4,5
1Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Elife
|July 18, 2023
Summary
The RNA-binding protein FUS suppresses toxic dipeptide repeat protein production in C9-ALS/FTD models by targeting GGGGCC repeat RNA. This discovery offers new therapeutic strategies for repeat expansion diseases.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Abnormal GGGGCC repeat expansions in the C9orf72 gene are a leading cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD).
- Repeat-associated non-AUG (RAN) translation converts these expansions into toxic dipeptide repeat proteins (DPRs), driving disease pathogenesis.
Purpose of the Study:
- To investigate the regulatory mechanisms of RAN translation, specifically the role of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs.
- To elucidate how RBPs influence DPR production and subsequent neurodegeneration in C9-ALS/FTD.
Main Methods:
- Utilized C9-ALS/FTD model flies to study the in vivo effects of RBPs on RAN translation and neurodegeneration.
- Employed in vitro assays to examine the direct interaction of the RBP FUS with GGGGCC repeat RNA and its structural modulation.
- Assessed the RNA-binding activity-dependent function of FUS in suppressing RAN translation.
Main Results:
- Demonstrated that the FUS protein suppresses RAN translation and neurodegeneration in a manner dependent on its RNA-binding activity.
- Identified that FUS directly binds to GGGGCC repeat RNA and modulates its G-quadruplex structure.
- Showed that FUS acts as an RNA chaperone to suppress RAN translation in vitro.
Conclusions:
- Revealed a novel regulatory mechanism for RAN translation involving G-quadruplex-targeting RBPs like FUS.
- Established FUS as a suppressor of RAN translation and neurodegeneration in C9-ALS/FTD.
- Provided potential therapeutic insights for C9-ALS/FTD and other repeat expansion disorders by targeting RBP-RNA interactions.
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