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

Bhuvaneish T. Selvaraj, Matthew R. Livesey, Chen Zhao, Jenna M. Gregory, Owain T. James, Elaine M. Cleary, Amit K. Chouhan, Angus B. Gane, Emma M. Perkins, Owen Dando, Simon G. Lillico, Youn-Bok Lee, Agnes L. Nishimura, Urjana Poreci, Sai Thankamony, Meryll Pray, Navneet A. Vasistha, Dario Magnani, Shyamanga Borooah, Karen Burr, David Story, Alexander McCampbell, Christopher E. Shaw, Peter C. Kind, Timothy J. Aitman, C. Bruce A. Whitelaw, Ian Wilmut, Colin Smith, Gareth B. Miles, Giles E. Hardingham, David J. A. Wyllie () and Siddharthan Chandran ()
Additional contact information
Bhuvaneish T. Selvaraj: University of Edinburgh
Matthew R. Livesey: University of Edinburgh
Chen Zhao: University of Edinburgh
Jenna M. Gregory: University of Edinburgh
Owain T. James: University of Edinburgh
Elaine M. Cleary: University of Edinburgh
Amit K. Chouhan: University of Edinburgh
Angus B. Gane: University of Edinburgh
Emma M. Perkins: University of Edinburgh
Owen Dando: University of Edinburgh
Simon G. Lillico: University of Edinburgh
Youn-Bok Lee: King’s College London
Agnes L. Nishimura: King’s College London
Urjana Poreci: Biogen
Sai Thankamony: Biogen
Meryll Pray: Biogen
Navneet A. Vasistha: University of Edinburgh
Dario Magnani: University of Edinburgh
Shyamanga Borooah: University of Edinburgh
Karen Burr: University of Edinburgh
David Story: University of Edinburgh
Alexander McCampbell: Biogen
Christopher E. Shaw: King’s College London
Peter C. Kind: University of Edinburgh
Timothy J. Aitman: University of Edinburgh
C. Bruce A. Whitelaw: University of Edinburgh
Ian Wilmut: University of Edinburgh
Colin Smith: University of Edinburgh
Gareth B. Miles: University of Edinburgh
Giles E. Hardingham: University of Edinburgh
David J. A. Wyllie: University of Edinburgh
Siddharthan Chandran: University of Edinburgh

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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 neurons (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.

Date: 2018
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DOI: 10.1038/s41467-017-02729-0

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