C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Article number | 347 |
Journal | Nature Communications |
Volume | 9 |
Issue number | 1 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 1 Dec 2018 |
Externally published | Yes |
Bibliographical note
Funding Information:
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).
Publisher Copyright:
© 2018 The Author(s).
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