TY - JOUR
T1 - C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity
AU - Selvaraj, Bhuvaneish T.
AU - Livesey, Matthew R.
AU - Zhao, Chen
AU - Gregory, Jenna M.
AU - James, Owain T.
AU - Cleary, Elaine M.
AU - Chouhan, Amit K.
AU - Gane, Angus B.
AU - Perkins, Emma M.
AU - Dando, Owen
AU - Lillico, Simon G.
AU - Lee, Youn Bok
AU - Nishimura, Agnes L.
AU - Poreci, Urjana
AU - Thankamony, Sai
AU - Pray, Meryll
AU - Vasistha, Navneet A.
AU - Magnani, Dario
AU - Borooah, Shyamanga
AU - Burr, Karen
AU - Story, David
AU - McCampbell, Alexander
AU - Shaw, Christopher E.
AU - Kind, Peter C.
AU - Aitman, Timothy J.
AU - Whitelaw, C. Bruce A.
AU - Wilmut, Ian
AU - Smith, Colin
AU - Miles, Gareth B.
AU - Hardingham, Giles E.
AU - Wyllie, David J.A.
AU - Chandran, Siddharthan
N1 - Funded by The Wellcome Trust (Grant 092742/Z/10/Z), MNDA (Miles/Oct14/878-792), MRC, Euan MacDonald Centre, UK DRI, DBT-India, ISSF (WT/UoE), Royal Society of Edinburgh (CRF), and Biogen/UoE Joint Discovery Research Collaboration. RNA-Seqraw reads were generated by Edinburgh Genomics, The University of Edinburgh. Edinburgh Genomics is partly supported through core grants from NERC (R8/H10/56), MRC (MR/K001744/1), and BBSRC (BB/J004243/1).
PY - 2018/1/24
Y1 - 2018/1/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041044335&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-02729-0
DO - 10.1038/s41467-017-02729-0
M3 - Article
C2 - 29367641
AN - SCOPUS:85041044335
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
M1 - 347
ER -