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Nat Commun. 2018 Jan 24;9(1):347. doi: 10.1038/s41467-017-02729-0.

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

Author information

1
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK.
2
Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, EH16 4SB, UK.
3
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
4
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK.
5
School of Psychology and Neuroscience, University of St Andrews, St Andrews, KY16 9JP, UK.
6
Centre for Brain Development and Repair, inStem, Bangalore, 560065, India.
7
The Roslin Institute and R(D)SVS, University of Edinburgh, Edinburgh, EH25 9RG, UK.
8
Maurice Wohl Clinical Neuroscience Institute, King's College London, London, SE5 8AF, UK.
9
Global Biomarker and Drug Discovery, Biogen, Cambridge, MA, 02142, USA.
10
Neurology Research, Biogen, Cambridge, MA, 02142, USA.
11
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
12
UK DRI Institute at Edinburgh, University of Edinburgh, Edinburgh, EH16 4UU, UK.
13
Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, EH16 4SB, UK. david.j.a.wyllie@ed.ac.uk.
14
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK. david.j.a.wyllie@ed.ac.uk.
15
Centre for Brain Development and Repair, inStem, Bangalore, 560065, India. david.j.a.wyllie@ed.ac.uk.
16
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK. siddharthan.chandran@ed.ac.uk.
17
Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, EH16 4SB, UK. siddharthan.chandran@ed.ac.uk.
18
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK. siddharthan.chandran@ed.ac.uk.
19
Centre for Brain Development and Repair, inStem, Bangalore, 560065, India. siddharthan.chandran@ed.ac.uk.
20
UK DRI Institute at Edinburgh, University of Edinburgh, Edinburgh, EH16 4UU, UK. siddharthan.chandran@ed.ac.uk.

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.

PMID:
29367641
PMCID:
PMC5783946
DOI:
10.1038/s41467-017-02729-0
[Indexed for MEDLINE]
Free PMC Article

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