eLife (Jul 2023)
FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD
- 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,
- Hideki Mochizuki,
- Hidehiro Mizusawa,
- Keiji Wada,
- Kinya Ishikawa,
- Osamu Onodera,
- Kazuhiko Nakatani,
- Leonard Petrucelli,
- Hideki Taguchi,
- Yoshitaka Nagai
Affiliations
- Yuzo Fujino
- ORCiD
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Morio Ueyama
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Taro Ishiguro
- Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Daisaku Ozawa
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Japan
- Hayato Ito
- ORCiD
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
- Toshihiko Sugiki
- ORCiD
- Laboratory of Molecular Biophysics, Institute for Protein Research, Osaka University, Osaka, Japan
- Asako Murata
- Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and28 Industrial Research, Osaka University, Osaka, Japan
- Akira Ishiguro
- Research Center for Micro-nano Technology, Hosei University, Tokyo, Japan
- Tania Gendron
- Department of Neuroscience, Mayo Clinic, Jacksonville, United States
- Kohji Mori
- ORCiD
- Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
- Eiichi Tokuda
- Department of Chemistry, Keio University, Kanagawa, Japan
- Tomoya Taminato
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Japan
- Takuya Konno
- Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata, Japan
- Akihide Koyama
- Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata, Japan
- Yuya Kawabe
- ORCiD
- Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
- Toshihide Takeuchi
- Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Japan; Life Science Research Institute, Kindai University, Osaka, Japan
- Yoshiaki Furukawa
- Department of Chemistry, Keio University, Kanagawa, Japan
- Toshimichi Fujiwara
- ORCiD
- Laboratory of Molecular Biophysics, Institute for Protein Research, Osaka University, Osaka, Japan
- Manabu Ikeda
- Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
- Toshiki Mizuno
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Hideki Mochizuki
- Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan
- Hidehiro Mizusawa
- Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Keiji Wada
- Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Kinya Ishikawa
- Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Osamu Onodera
- ORCiD
- Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata, Japan
- Kazuhiko Nakatani
- Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and28 Industrial Research, Osaka University, Osaka, Japan
- Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic, Jacksonville, United States
- Hideki Taguchi
- ORCiD
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan; Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa, Japan
- Yoshitaka Nagai
- ORCiD
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan
- DOI
- https://doi.org/10.7554/eLife.84338
- Journal volume & issue
-
Vol. 12
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.
Keywords
