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

摘要

Mutations in 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 mutations that leads to increased Ca-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 patient post mortem material. We therefore present multiple lines of evidence for the specific upregulation of GluA1 subunits in human mutant MNs that could lead to a potential pathogenic excitotoxic mechanism in ALS.