C9ORF72 repeat expansion causes vulnerability of motor

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Authors

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, Siddharthan Chandran

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.

PMID:29367641 | DOI:10.1038/s41467-017-02729-0