@article{c8891012d6ad485f9b826cb70853a306,
title = "Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS",
abstract = "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. 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.",
keywords = "ALS, C9ORF72, DPR, Drosophila, FTD, RNA foci, Ran translation, Repeats",
author = "Helene Tran and Sandra Almeida and Jill Moore and Gendron, {Tania F.} and Chalasani, {Uma Devi} and Yubing Lu and Xing Du and Nickerson, {Jeffrey A.} and Leonard Petrucelli and Zhiping Weng and Gao, {Fen Biao}",
note = "Funding Information: We thank F. Ladam, P.-H. Wu, E. Ricci, Z. Zhang, S. Ordway, and Gao lab members for comments; the Bloomington Drosophila Stock Center for 36R and other fly lines; and the UMMS Department of Cell and Developmental Biology Confocal Core for use of their microscopes. We also thank L. Ranum for anti-GR antibody, E. Baehrecke for anti-p62 antibody, and W. Seeley (Neurodegenerative Disease Brain Bank at the University of California, San Francisco) for brain tissues of C9ORF72 patients. This work was supported by an ALS Association Milton Safenowitz Postdoctoral Fellowship (H.T.); a grant from ALS Therapy Alliance (F.-B.G.); Mayo Clinic Foundation (L.P.); grants from the Department of Defense (ALSRP AL130125), the ALS Association, Packard Center for ALS Research and Target ALS (F.-B.G. and L.P.). This work was also supported by grants from the National Institutes of Health: R01NS057553, R01NS079725, and R21NS086318 (F.-B.G.); P50AG016574, R21NS084528, R01NS088689, and R01NS063964; R01NS077402 and P01NS084974 (L.P.); P01HD078253 (Z.W.); and R21NS089979 (T.F.G.). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = sep,
day = "23",
doi = "10.1016/j.neuron.2015.09.015",
language = "English (US)",
volume = "87",
pages = "1207--1214",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "6",
}