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C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca 2+ -permeable AMPA receptor-mediated excitotoxicity.
- Source :
-
Nature communications [Nat Commun] 2018 Jan 24; Vol. 9 (1), pp. 347. Date of Electronic Publication: 2018 Jan 24. - Publication Year :
- 2018
-
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 <superscript>2+</superscript> -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 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
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 29367641
- Full Text :
- https://doi.org/10.1038/s41467-017-02729-0