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- Title
FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD.
- Authors
Yuzo Fujino; Morio Ueyama; Taro Ishiguro; Daisaku Ozawa; Hayato Ito; Toshihiko Sugiki; Asako Murata; Akira Ishiguro; Tania Gendron; Kohji Mori; Eiichi Tokuda; Tomoya Taminato; Takuya Konno; Akihide Koyama; Yuya Kawabe; Toshihide Takeuchi; Yoshiaki Furukawa; Toshimichi Fujiwara; Manabu Ikeda; Toshiki Mizuno
- Abstract
Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.
- Subjects
AMYOTROPHIC lateral sclerosis; RNA; RNA-binding proteins; FRONTOTEMPORAL dementia; QUADRUPLEX nucleic acids
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.84338