@article{ab57e51df77d473886dfe4979529dd95,
title = "A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism",
abstract = "The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine–arginine and proline–arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.",
keywords = "ALS, C9orf72, DPR, Pur-alpha, RNA toxicity, Zebrafish, p62",
author = "Bart Swinnen and Andre Bento-Abreu and Gendron, {Tania F.} and Steven Boeynaems and Elke Bogaert and Rik Nuyts and Mieke Timmers and Wendy Scheveneels and Nicole Hersmus and Jiou Wang and Sarah Mizielinska and Isaacs, {Adrian M.} and Leonard Petrucelli and Robin Lemmens and {Van Damme}, Philip and {Van Den Bosch}, Ludo and Wim Robberecht",
note = "Funding Information: Acknowledgements This work was supported by the European Research Council under the European{\textquoteright}s Seventh Framework Programme (FP7/2007–2013) under the Euro-MOTOR project, Grant agreement no. 259867, and the ERC Grant agreement no. 340429, the Research Foundation Flanders (FWO Flanders, G.0983.14N), the University of Leuven [GOA/11/014, C14/17/107 and the {\textquoteleft}Opening the Future{\textquoteright} fund], the Interuniversity Attraction Poles program [P7/16] of the Belgian Federal Science Policy Office, the ALS Liga (Belgium) and the Association Belge contre les Maladies Neuro-Musculaires (ABMM). WR is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders and the {\textquoteleft}Hart voor ALS{\textquoteright} Fund, KU Leuven. SB was supported by the Agency for Innovation by Science and Technology (IWT) Flanders. BS is a PhD Fellow, EB was a Postdoctoral Fellow and both PVD and RL are Senior Clinical Investigators of FWO Flanders. We are grateful to Dr. M. Yamakawa (Keio University School of Medicine, Tokyo, Japan) for sharing the GP construct. Funding Information: This work was supported by the European Research Council under the European?s Seventh Framework Programme (FP7/2007?2013) under the Euro-MOTOR project, Grant agreement no. 259867, and the ERC Grant agreement no. 340429, the Research Foundation Flanders (FWO Flanders, G.0983.14N), the University of Leuven [GOA/11/014, C14/17/107 and the ?Opening the Future? fund], the Interuniversity Attraction Poles program [P7/16] of the Belgian Federal Science Policy Office, the ALS Liga (Belgium) and the Association Belge contre les Maladies Neuro-Musculaires (ABMM). WR is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders and the ?Hart voor ALS? Fund, KU Leuven. SB was supported by the Agency for Innovation by Science and Technology (IWT) Flanders. BS is a PhD Fellow, EB was a Postdoctoral Fellow and both PVD and RL are Senior Clinical Investigators of FWO Flanders. We are grateful to Dr. M. Yamakawa (Keio University School of Medicine, Tokyo, Japan) for sharing the GP construct. The authors declare that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = mar,
day = "1",
doi = "10.1007/s00401-017-1796-5",
language = "English (US)",
volume = "135",
pages = "427--443",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "3",
}