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C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity

Research output: Contribution to journalArticle

Author(s)

  • Youn-Bok Lee
  • Pranetha Baskaran
  • Jorge Gomez-Deza
  • Han-Jou Chen
  • Agnes L Nishimura
  • Bradley N Smith
  • Claire Troakes
  • Yoshitsugu Adachi
  • Alan Stepto
  • Leonard Petrucelli
  • Jean-Marc Gallo
  • Frank Hirth
  • Boris Rogelj
  • Sarah Guthrie
  • Christopher E Shaw

Department/unit(s)

Publication details

JournalHuman Molecular Genetics
DateAccepted/In press - 29 Aug 2017
DatePublished (current) - 15 Dec 2017
Issue number24
Volume26
Number of pages13
Pages (from-to)4765-4777
Original languageEnglish

Abstract

An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culture model activates programmed cell death and TDP-43 cleavage in a dose-dependent manner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being the most toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a key mediator of cytotoxicity and that cross-talk between DPR proteins likely modifies their pathogenic status in C9ALS/FTD.

Bibliographical note

© The Author 2017. Published by Oxford University Press.

    Research areas

  • Journal Article

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