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.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Tran
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Moore
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: UmaDevi
authors.initials: U
authors.lastname: Chalasani
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Yubing
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nickerson
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: fen-biao.gao@umassmed.edu.
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D000073885:C9orf72 Protein; D004151:Dipeptides / Q000096:biosynthesis* / Q000633:toxicity; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000633:toxicity; D057180:Frontotemporal Dementia / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011506:Proteins / Q000378:metabolism*; D015138:RNA, Nuclear / Q000096:biosynthesis* / Q000633:toxicity
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D029721:Drosophila Proteins; D011506:Proteins; D015138:RNA, Nuclear
keywords: ALS; C9ORF72; DPR; Drosophila; FTD; RNA foci; Ran translation; repeats