Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD

被引:48
作者
Moens, Thomas G. [1 ,2 ]
Mizielinska, Sarah [1 ,3 ,4 ]
Niccoli, Teresa [1 ,2 ]
Mitchell, Jamie S. [1 ]
Thoeng, Annora [1 ]
Ridler, Charlotte E. [1 ]
Gronke, Sebastian [5 ]
Esser, Jacqueline [5 ]
Heslegrave, Amanda [6 ,8 ]
Zetterberg, Henrik [6 ,7 ,8 ]
Partridge, Linda [2 ,5 ]
Isaacs, Adrian M. [1 ,8 ]
机构
[1] UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England
[2] UCL, Inst Hlth Ageing, Dept Genet Evolut & Environm, London WC1E 6BT, England
[3] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, Maurice Wohl Clin Neurosci Inst, London SE5 9RT, England
[4] Kings Coll London, UK Dementia Res Inst, Inst Psychiat Psychol & Neurosci, Maurice Wohl Clin Neurosci Inst, London SE5 9RT, England
[5] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany
[6] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 1PJ, England
[7] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Clin Neurochem Lab,Dept Psychiat & Neurochem, Gothenburg, Sweden
[8] UCL, UCL Inst Neurol, UK Dementia Res Inst, London WC1N 3BG, England
基金
英国惠康基金; 欧洲研究理事会;
关键词
C9orf72; Drosophila; ALS; FTD; Repeat expansion; DIPEPTIDE-REPEAT PROTEINS; HEXANUCLEOTIDE REPEAT; GGGGCC REPEAT; FRONTOTEMPORAL DEMENTIA; C9ORF72; ABLATION; EXPANSION; FOCI; ALS; TRANSCRIPTS; TRANSPORT;
D O I
10.1007/s00401-017-1798-3
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Neurodegeneration may occur via transcription of the repeats into inherently toxic repetitive sense and antisense RNA species, or via repeat-associated non-ATG initiated translation (RANT) of sense and antisense RNA into toxic dipeptide repeat proteins. We have previously demonstrated that regular interspersion of repeat RNA with stop codons prevents RANT (RNA-only models), allowing us to study the role of repeat RNA in isolation. Here we have created novel RNA-only Drosophila models, including the first models of antisense repeat toxicity, and flies expressing extremely large repeats, within the range observed in patients. We generated flies expressing similar to 100 repeat sense or antisense RNA either as part of a processed polyadenylated transcript or intronic sequence. We additionally created Drosophila expressing >1000 RNA-only repeats in the sense direction. When expressed in adult Drosophila neurons polyadenylated repeat RNA is largely cytoplasmic in localisation, whilst intronic repeat RNA forms intranuclear RNA foci, as does >1000 repeat RNA, thus allowing us to investigate both nuclear and cytoplasmic RNA toxicity. We confirmed that these RNA foci are capable of sequestering endogenous Drosophila RNA-binding proteins, and that the production of dipeptide proteins (poly-glycine-proline, and poly-glycine-arginine) is suppressed in our models. We find that neither cytoplasmic nor nuclear sense or antisense RNA are toxic when expressed in adult Drosophila neurons, suggesting they have a limited role in disease pathogenesis.
引用
收藏
页码:445 / 457
页数:13
相关论文
共 59 条
  • [31] Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis
    Ling, Shuo-Chien
    Polymenidou, Magdalini
    Cleveland, Don W.
    [J]. NEURON, 2013, 79 (03) : 416 - 438
  • [32] C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD
    Liu, Yuanjing
    Pattamatta, Amrutha
    Zu, Tao
    Reid, Tammy
    Bardhi, Olgert
    Borchelt, David R.
    Yachnis, Anthony T.
    Ranum, Laura P. W.
    [J]. NEURON, 2016, 90 (03) : 521 - 534
  • [33] Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
    Majounie, Elisa
    Renton, Alan E.
    Mok, Kin
    Dopper, Elise G. P.
    Waite, Adrian
    Rollinson, Sara
    Chio, Adrian
    Restagno, Gabriella
    Nicolaou, Nayia
    Simon-Sanchez, Javier
    van Swieten, John C.
    Abramzon, Yevgeniya
    Johnson, Janel O.
    Sendtner, Michael
    Pamphlett, Roger
    Orrell, Richard W.
    Mead, Simon
    Sidle, Katie C.
    Houlden, Henry
    Rohrer, Jonathan D.
    Morrison, Karen E.
    Pall, Hardev
    Talbot, Kevin
    Ansorge, Olaf
    Hernandez, Dena G.
    Arepalli, Sampath
    Sabatelli, Mario
    Mora, Gabriele
    Corbo, Massimo
    Giannini, Fabio
    Calvo, Andrea
    Englund, Elisabet
    Borghero, Giuseppe
    Foris, Gian Luca
    Remes, Anne M.
    Laaksovirta, Hannu
    McCluskey, Leo
    Trojanowski, John Q.
    Van Deerlin, Vivianna M.
    Schellenberg, Gerard D.
    Nalls, Michael A.
    Drory, Vivian E.
    Lu, Chin-Song
    Yeh, Tu-Hsueh
    Ishiura, Hiroyuki
    Takahashi, Yuji
    Tsuji, Shoji
    Le Ber, Isabelle
    Brice, Alexis
    Drepper, Carsten
    [J]. LANCET NEUROLOGY, 2012, 11 (04) : 323 - 330
  • [34] Exploiting position effects and the gypsy retrovirus insulator to engineer precisely expressed transgenes
    Markstein, Michele
    Pitsouli, Chrysoula
    Villalta, Christians
    Celniker, Susan E.
    Perrimon, Norbert
    [J]. NATURE GENETICS, 2008, 40 (04) : 476 - 483
  • [35] Mizielinska S, 2014, SCIENCE, V16, P1131
  • [36] C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci
    Mizielinska, Sarah
    Lashley, Tammaryn
    Norona, Frances E.
    Clayton, Emma L.
    Ridler, Charlotte E.
    Fratta, Pietro
    Isaacs, Adrian M.
    [J]. ACTA NEUROPATHOLOGICA, 2013, 126 (06) : 845 - 857
  • [37] Genetic models of C9orf72: what is toxic?
    Moens, Thomas G.
    Partridge, Linda
    Isaacs, Adrian M.
    [J]. CURRENT OPINION IN GENETICS & DEVELOPMENT, 2017, 44 : 92 - 101
  • [38] The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
    Mori, Kohji
    Weng, Shih-Ming
    Arzberger, Thomas
    May, Stephanie
    Rentzsch, Kristin
    Kremmer, Elisabeth
    Schmid, Bettina
    Kretzschmar, Hans A.
    Cruts, Marc
    Van Broeckhoven, Christine
    Haass, Christian
    Edbauer, Dieter
    [J]. SCIENCE, 2013, 339 (6125) : 1335 - 1338
  • [39] Niccoli T, 2016, CURR BIOL, V26, P2291, DOI [10.1016/j.cub.2016.09.018, 10.1016/j.cub.2016.07.017]
  • [40] C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD
    O'Rourke, Jacqueline G.
    Bogdanik, Laurent
    Muhammad, A. K. M. G.
    Gendron, Tania F.
    Kim, Kevin J.
    Austin, Andrew
    Cady, Janet
    Liu, Elaine Y.
    Zarrow, Jonah
    Grant, Sharday
    Ho, Ritchie
    Bell, Shaughn
    Carmona, Sharon
    Simpkinson, Megan
    Lall, Deepti
    Wu, Kathryn
    Daughrity, Lillian
    Dickson, Dennis W.
    Harms, Matthew B.
    Petrucelli, Leonard
    Lee, Edward B.
    Lutz, Cathleen M.
    Baloh, Robert H.
    [J]. NEURON, 2015, 88 (05) : 892 - 901