Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS

Neuron. 2015 Sep 23;87(6):1207-1214. doi: 10.1016/j.neuron.2015.09.015.


Dipeptide repeat (DPR) proteins are toxic in various models of FTD/ALS with GGGGCC (G4C2) repeat expansion. However, it is unclear whether nuclear G4C2 RNA foci also induce neurotoxicity. Here, we describe a Drosophila model expressing 160 G4C2 repeats (160R) flanked by human intronic and exonic sequences. Spliced intronic 160R formed nuclear G4C2 sense RNA foci in glia and neurons about ten times more abundantly than in human neurons; however, they had little effect on global RNA processing and neuronal survival. In contrast, highly toxic 36R in the context of poly(A)(+) mRNA were exported to the cytoplasm, where DPR proteins were produced at >100-fold higher level than in 160R flies. Moreover, the modest toxicity of intronic 160R expressed at higher temperature correlated with increased DPR production, but not RNA foci. Thus, nuclear RNA foci are neutral intermediates or possibly neuroprotective through preventing G4C2 RNA export and subsequent DPR production.

Keywords: ALS; C9ORF72; DPR; Drosophila; FTD; RNA foci; Ran translation; repeats.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Animals, Genetically Modified
  • C9orf72 Protein
  • Dipeptides / biosynthesis*
  • Dipeptides / toxicity
  • Disease Models, Animal*
  • Drosophila
  • Drosophila Proteins / biosynthesis
  • Drosophila Proteins / toxicity
  • Frontotemporal Dementia / metabolism*
  • Frontotemporal Dementia / pathology
  • Humans
  • Proteins / metabolism*
  • RNA, Nuclear / biosynthesis*
  • RNA, Nuclear / toxicity


  • C9orf72 Protein
  • C9orf72 protein, human
  • Dipeptides
  • Drosophila Proteins
  • Proteins
  • RNA, Nuclear

Associated data

  • GEO/GSE72771