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

Bhuvaneish Thangaraj Selvaraj , Matthew Livesey , Chen Zhao , Jenna Gregory , Owain James, Elaine Cleary, Amit Kumar Chouhan, Angus Gane, Emma Perkins, Owen Dando, Simon Lillico, Youn-Bok Lee, Agnes Nishimura, Urjana Poreci, Sai Thankamony, Meryll Pray, Navneet Vasistha, Dario Magnani, Shyamanga Borooah, Karen BurrDavid Story, Alexander McCampbell, Christopher Shaw, Peter Kind, Timothy J. Aitman, Bruce Whitelaw, Ian Wilmut, Colin Smith, Gareth B. Miles, Giles Hardingham, David Wyllie, Siddharthan Chandran

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132 Citations (Scopus)


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.
Original languageEnglish
Article number347
Number of pages14
JournalNature Communications
Early online date24 Jan 2018
Publication statusE-pub ahead of print - 24 Jan 2018


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