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C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity

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Selvaraj_2018_NatComms_C9ORF72_CC.pdf (5.305Mb)
Date
24/01/2018
Author
Thangaraj Selvaraj , Bhuvaneish
Livesey , Matthew
Zhao , Chen
Gregory , Jenna
James, Owain
Cleary, Elaine
Chouhan, Amit Kumar
Gane, Angus
Perkins, Emma
Dando, Owen
Lillico, Simon
Lee, Youn-Bok
Nishimura, Agnes
Poreci, Urjana
Thankamony, Sai
Pray, Meryll
Vasistha, Navneet
Magnani, Dario
Borooah, Shyamanga
Burr, Karen
Story, David
McCampbell, Alexander
Shaw, Christopher
Kind, Peter
Aitman, Timothy J.
Whitelaw, Bruce
Wilmut, Ian
Smith, Colin
Miles, Gareth B.
Hardingham, Giles
Wyllie, David
Chandran, Siddharthan
Funder
Motor Neurone Disease Association
Grant ID
N/A
Keywords
RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
DAS
BDC
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Abstract
Mutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination of RNA-seq and electrophysiological studies on induced pluripotent stem cell (iPSC) derived motor neuron (MNs), we show that increased expression of GluA1 AMPA receptor (AMPAR) subunit occurs in MNs with C9ORF72 mutations that leads to increased Ca2+-permeable AMPAR expression and results in enhanced selective MN vulnerability to excitotoxicity. These deficits are not found in iPSC-derived cortical neurons and are abolished by CRISPR/Cas9-mediated correction of the C9ORF72 repeat expansion in MNs. We also demonstrate that MN-specific dysregulation of AMPAR expression is also present in C9ORF72 patient post mortem material. We therefore present multiple lines of evidence for the specific upregulation of GluA1 subunits in human mutant C9ORF72 MNs that could lead to a potential pathogenic excitotoxic mechanism in ALS.
Citation
Thangaraj Selvaraj , B , Livesey , M , Zhao , C , Gregory , J , James , O , Cleary , E , Chouhan , A K , Gane , A , Perkins , E , Dando , O , Lillico , S , Lee , Y-B , Nishimura , A , Poreci , U , Thankamony , S , Pray , M , Vasistha , N , Magnani , D , Borooah , S , Burr , K , Story , D , McCampbell , A , Shaw , C , Kind , P , Aitman , T J , Whitelaw , B , Wilmut , I , Smith , C , Miles , G B , Hardingham , G , Wyllie , D & Chandran , S 2018 , ' C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca 2+ -permeable AMPA receptor-mediated excitotoxicity ' , Nature Communications , vol. 9 , 347 . https://doi.org/10.1038/s41467-017-02729-0
Publication
Nature Communications
Status
Peer reviewed
DOI
https://doi.org/10.1038/s41467-017-02729-0
ISSN
2041-1723
Type
Journal article
Rights
© The Author(s) 2018. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Description
Funded by The Wellcome Trust (Grant 092742/Z/10/Z), MNDA (Miles/Oct14/878-792), MRC, Euan MacDonald Centre, UK DRI, DBT-India, ISSF (WT/UoE), Royal Society of Edinburgh (CRF), and Biogen/UoE Joint Discovery Research Collaboration. RNA-Seq raw reads were generated by Edinburgh Genomics, The University of Edinburgh. Edinburgh Genomics is partly supported through core grants from NERC (R8/H10/56), MRC (MR/K001744/1), and BBSRC (BB/J004243/1).
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/12606

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