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Open Access 01-03-2018 | Original Paper

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

Authors: 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

Published in: Acta Neuropathologica | Issue 3/2018

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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Title: A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism
Authors: 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
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1796-5

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

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