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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2015-09, Vol.87 (6), p.1207-1214
• Main Authors: Tran, Helene, Almeida, Sandra, Moore, Jill, Gendron, Tania F., Chalasani, UmaDevi, Lu, Yubing, Du, Xing, Nickerson, Jeffrey A., Petrucelli, Leonard, Weng, Zhiping, Gao, Fen-Biao
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Animals, Genetically Modified; C9ORF72; C9orf72 Protein; Cytoplasm; Dipeptides - biosynthesis; Dipeptides - toxicity; Disease Models, Animal; DPR; Drosophila; Drosophila Proteins - biosynthesis; Drosophila Proteins - toxicity; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; FTD; Gene expression; Humans; Insects; Neurons; Patients; Proteins; Proteins - metabolism; Ran translation; repeats; RNA foci; RNA, Nuclear - biosynthesis; RNA, Nuclear - toxicity; Rodents; Toxicity
• ISSN: 0896-6273; 1097-4199
• 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. •Intronic 160R form abundant nuclear sense RNA foci in Drosophila•Nuclear RNA foci cause little toxicity and minimal changes in RNA processing•Cytoplasmic 36R-poly(A) produce >100-fold more poly(GP) than intronic 160R•Modest toxicity of 160R at higher temperature correlates with increased DPRs Tran et al. engineered a novel Drosophila model of FTD/ALS with C9ORF72 repeat expansion and revealed that dipeptide repeat proteins, but not nuclear G4C2 repeat RNA foci, are a major source of toxicity in vivo.