C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity
Date
24/01/2018Author
Grant ID
N/A
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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
ISSN
2041-1723Type
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
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