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RNA-mediated toxicity in C9orf72 ALS and FTD.

Authors
  • McEachin, Zachary T1
  • Parameswaran, Janani2
  • Raj, Nisha3
  • Bassell, Gary J4
  • Jiang, Jie5
  • 1 Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA. Electronic address: [email protected]
  • 2 Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • 3 Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • 4 Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA.
  • 5 Department of Cell Biology, Emory University, Atlanta, GA 30322, USA. Electronic address: [email protected]
Type
Published Article
Journal
Neurobiology of Disease
Publisher
Elsevier
Publication Date
Aug 21, 2020
Volume
145
Pages
105055–105055
Identifiers
DOI: 10.1016/j.nbd.2020.105055
PMID: 32829028
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

A GGGGCC hexanucleotide repeat expansion in the first intron of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Compelling evidence suggests that gain of toxicity from the bidirectionally transcribed repeat expanded RNAs plays a central role in disease pathogenesis. Two potential mechanisms have been proposed including RNA-mediated toxicity and/or the production of toxic dipeptide repeat proteins. In this review, we focus on the role of RNA mediated toxicity in ALS/FTD caused by the C9orf72 mutation and discuss arguments for and against this mechanism. In addition, we summarize how G4C2 repeat RNAs can elicit toxicity and potential therapeutic strategies to mitigate RNA-mediated toxicity. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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