C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity.
Bhuvaneish T SelvarajMatthew R LiveseyChen ZhaoJenna M GregoryOwain T JamesElaine M ClearyAmit K ChouhanAngus B GaneEmma M PerkinsOwen R DandoSimon G LillicoYoun-Bok LeeAgnes L NishimuraUrjana PoreciSai ThankamonyMeryll PrayNavneet A VasisthaDario MagnaniShyamanga BorooahKaren BurrDavid StoryAlexander McCampbellChristopher E ShawPeter C KindTimothy J AitmanC Bruce A WhitelawIan WilmutColin SmithGareth B MilesGiles E HardinghamDavid J A WyllieSiddharthan ChandranPublished in: Nature communications (2018)
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.
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