1. C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca 2+ -permeable AMPA receptor-mediated excitotoxicity.
- Author
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Selvaraj BT, Livesey MR, Zhao C, Gregory JM, James OT, Cleary EM, Chouhan AK, Gane AB, Perkins EM, Dando O, Lillico SG, Lee YB, Nishimura AL, Poreci U, Thankamony S, Pray M, Vasistha NA, Magnani D, Borooah S, Burr K, Story D, McCampbell A, Shaw CE, Kind PC, Aitman TJ, Whitelaw CBA, Wilmut I, Smith C, Miles GB, Hardingham GE, Wyllie DJA, and Chandran S
- Subjects
- Amyotrophic Lateral Sclerosis genetics, C9orf72 Protein metabolism, CRISPR-Cas Systems, Calcium metabolism, DNA Repeat Expansion, Gene Targeting, Humans, Receptors, AMPA genetics, Spinal Cord metabolism, Spinal Cord physiopathology, C9orf72 Protein genetics, Motor Neurons pathology, Receptors, AMPA metabolism
- 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 Ca
2+ -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.- Published
- 2018
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