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A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

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Bart Swinnen, Andre Bento-Abreu, Tania F Gendron, Steven Boeynaems, Elke Bogaert, Rik Nuyts, Mieke Timmers, Wendy Scheveneels, Nicole Hersmus, Jiou Wang, Sarah Mizielinska, Adrian M Isaacs, Leonard Petrucelli, Robin Lemmens, Philip Van Damme, Ludo Van Den Bosch, Wim Robberecht

Original languageEnglish
Pages (from-to)427-443
Number of pages17
JournalActa Neuropathologica
Volume135
Issue number3
Early online date4 Jan 2018
DOIs
Accepted/In press14 Dec 2017
E-pub ahead of print4 Jan 2018
PublishedMar 2018

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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.

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