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- Title
A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism.
- Authors
Swinnen, Bart; Bento-Abreu, Andre; Gendron, Tania F.; Boeynaems, Steven; Bogaert, Elke; Nuyts, Rik; Timmers, Mieke; Scheveneels, Wendy; Hersmus, Nicole; Wang, Jiou; Mizielinska, Sarah; Isaacs, Adrian M.; Petrucelli, Leonard; Lemmens, Robin; Van Damme, Philip; Van Den Bosch, Ludo; Robberecht, Wim
- Abstract
The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in <italic>C9orf72</italic> 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 <italic>C9orf72</italic>-associated ALS/FTD.
- Subjects
AMYOTROPHIC lateral sclerosis; NEURODEGENERATION
- Publication
Acta Neuropathologica, 2018, Vol 135, Issue 3, p427
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-017-1796-5