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

Acta Neuropathol. 2018 Mar;135(3):427-443. doi: 10.1007/s00401-017-1796-5. Epub 2018 Jan 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Animals, Genetically Modified
  • Axons / metabolism
  • Axons / pathology
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • DNA Repeat Expansion
  • Disease Models, Animal
  • Escherichia coli
  • Gene Transfer Techniques
  • Humans
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • RNA / metabolism*
  • Zebrafish


  • C9orf72 Protein
  • RNA