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- Title
C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca<sup>2+</sup>-permeable AMPA receptor-mediated excitotoxicity.
- Authors
Selvaraj, Bhuvaneish T.; Livesey, Matthew R.; Chen Zhao; Gregory, Jenna M.; James, Owain T.; Cleary, Elaine M.; Chouhan, Amit K.; Gane, Angus B.; Perkins, Emma M.; Dando, Owen; Lillico, Simon G.; Youn-Bok Lee; Nishimura, Agnes L.; Poreci, Urjana; Thankamony, Sai; Pray, Meryll; Vasistha, Navneet A.; Magnani, Dario; Borooah, Shyamanga; Burr, Karen
- 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 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.
- Subjects
AMYOTROPHIC lateral sclerosis; MOTOR neuron diseases; MOTOR neurons; INDUCED pluripotent stem cells; AMPA receptors
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-017-02729-0