Swinnen, B;
Bento-Abreu, A;
Gendron, TF;
Boeynaems, S;
Bogaert, E;
Nuyts, R;
Timmers, M;
... Robberecht, W; + view all
(2018)
A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism.
Acta Neuropathologica
10.1007/s00401-017-1796-5.
(In press).
Preview |
Text
10.1007%2Fs00401-017-1796-5.pdf - Published Version Download (2MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism |
| Location: | Germany |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s00401-017-1796-5 |
| Publisher version: | http://doi.org/10.1007/s00401-017-1796-5 |
| Language: | English |
| Additional information: | Copyright information © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
| Keywords: | ALS, C9orf72, DPR, Pur-alpha, RNA toxicity, Zebrafish, p62 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10041577 |
Archive Staff Only
 |
View Item |
