Citations 4
Author Response: FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD
Fujino, Yuzo , Ishiguro, Taro , Ozawa, Daisaku, Ito, Hayato , Taminato, Tomoya , Kawabe, Yuya , Takeuchi, Toshihide , Ikeda, Manabu , Mizusawa, Hidehiro, Wada, Keiji , Ishikawa, Kinya , Petrucelli, Leonard , Ueyama, Morio , Sugiki, Toshihiko , Murata, Asako , Ishiguro, Akira , Gendron, Tania F. , Mori, Kohji , Tokuda, Eiichi , Konno, Takuya , Koyama, Akihide , Furukawa, Yoshiaki , Fujiwara, Toshimichi , Mizuno, Toshiki , Mochizuki, Hideki , Onodera, Osamu , Nakatani, Kazuhiko , Taguchi, Hideki , Nagai, Yoshitaka
No container title available | July 18, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD
Fujino, Yuzo , Ishiguro, Taro , Ozawa, Daisaku, Ito, Hayato , Sugiki, Toshihiko , Mori, Kohji , Taminato, Tomoya , Kawabe, Yuya , Takeuchi, Toshihide , Ikeda, Manabu , Mizusawa, Hidehiro, Wada, Keiji , Ishikawa, Kinya , Petrucelli, Leonard , Ito, Hayato , Sugiki, Toshihiko , Mori, Kohji , Ueyama, Morio , Murata, Asako , Ishiguro, Akira , Gendron, Tania F. , Tokuda, Eiichi , Konno, Takuya , Koyama, Akihide , Furukawa, Yoshiaki , Fujiwara, Toshimichi , Mizuno, Toshiki , Mochizuki, Hideki , Onodera, Osamu , Nakatani, Kazuhiko , Taguchi, Hideki , Nagai, Yoshitaka
eLife | July 18, 2023 | Volume: 12 | Issue: No issue available | Pages: No page available
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.
FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD
Fujino, Yuzo , Ishiguro, Taro , Ozawa, Daisaku, Ito, Hayato , Sugiki, Toshihiko , Mori, Kohji , Taminato, Tomoya , Kawabe, Yuya , Takeuchi, Toshihide , Ikeda, Manabu , Mizusawa, Hidehiro, Wada, Keiji , Ishikawa, Kinya , Petrucelli, Leonard , Sugiki, Toshihiko , Mori, Kohji , Ueyama, Morio , Murata, Asako , Ishiguro, Akira , Gendron, Tania F. , Tokuda, Eiichi , Konno, Takuya , Koyama, Akihide , Furukawa, Yoshiaki , Fujiwara, Toshimichi , Mizuno, Toshiki , Mochizuki, Hideki , Onodera, Osamu , Nakatani, Kazuhiko , Taguchi, Hideki , Nagai, Yoshitaka
No container title available | June 20, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
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.
FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD
Fujino, Yuzo , Ishiguro, Taro , Ozawa, Daisaku, Ito, Hayato , Sugiki, Toshihiko , Murata, Asako, Mori, Kohji , Taminato, Tomoya , Koyama, Akihide , Kawabe, Yuya , Takeuchi, Toshihide , Ikeda, Manabu , Mizusawa, Hidehiro, Wada, Keiji , Ishikawa, Kinya , Petrucelli, Leonard , Taguchi, Hideki , Murata, Asako , Ito, Hayato , Sugiki, Toshihiko , Gendron, Tania, Mori, Kohji , Kawabe, Yuya , Fujiwara, Toshimichi , Onodera, Osamu , Taguchi, Hideki , Nagai, Yoshitaka , Ueyama, Morio , Ishiguro, Akira , Gendron, Tania F. , Tokuda, Eiichi , Konno, Takuya , Furukawa, Yoshiaki , Mizuno, Toshiki , Mochizuki, Hideki , Onodera, Osamu , Nakatani, Kazuhiko
eLife | February 13, 2023 | Volume: 12 | Issue: No issue available | Pages: No page available
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.