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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. / Selvaraj, Bhuvaneish T.; Livesey, Matthew R.; Zhao, Chen; Gregory, Jenna M.; James, Owain T.; Cleary, Elaine M.; Chouhan, Amit K.; Gane, Angus B.; Perkins, Emma M.; Dando, Owen; Lillico, Simon G.; Lee, Youn Bok; Nishimura, Agnes L.; Poreci, Urjana; Thankamony, Sai; Pray, Meryll; Vasistha, Navneet A.; Magnani, Dario; Borooah, Shyamanga; Burr, Karen; Story, David; McCampbell, Alexander; Shaw, Christopher E.; Kind, Peter C.; Aitman, Timothy J.; Whitelaw, C. Bruce A.; Wilmut, Ian; Smith, Colin; Miles, Gareth B.; Hardingham, Giles E.; Wyllie, David J.A.; Chandran, Siddharthan.

In: Nature Communications, Vol. 9, No. 1, 347, 01.12.2018.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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 & Chandran, S 2018, 'C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity', Nature Communications, vol. 9, no. 1, 347. https://doi.org/10.1038/s41467-017-02729-0

APA

Selvaraj, B. T., Livesey, M. R., Zhao, C., Gregory, J. M., James, O. T., Cleary, E. M., Chouhan, A. K., Gane, A. B., Perkins, E. M., Dando, O., Lillico, S. G., Lee, Y. B., Nishimura, A. L., Poreci, U., Thankamony, S., Pray, M., Vasistha, N. A., Magnani, D., Borooah, S., ... Chandran, S. (2018). C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. Nature Communications, 9(1), [347]. https://doi.org/10.1038/s41467-017-02729-0

Vancouver

Selvaraj BT, Livesey MR, Zhao C, Gregory JM, James OT, Cleary EM et al. C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. Nature Communications. 2018 Dec 1;9(1). 347. https://doi.org/10.1038/s41467-017-02729-0

Author

Selvaraj, Bhuvaneish T. ; Livesey, Matthew R. ; Zhao, Chen ; Gregory, Jenna M. ; James, Owain T. ; Cleary, Elaine M. ; Chouhan, Amit K. ; Gane, Angus B. ; Perkins, Emma M. ; Dando, Owen ; Lillico, Simon G. ; Lee, Youn Bok ; Nishimura, Agnes L. ; Poreci, Urjana ; Thankamony, Sai ; Pray, Meryll ; Vasistha, Navneet A. ; Magnani, Dario ; Borooah, Shyamanga ; Burr, Karen ; Story, David ; McCampbell, Alexander ; Shaw, Christopher E. ; Kind, Peter C. ; Aitman, Timothy J. ; Whitelaw, C. Bruce A. ; Wilmut, Ian ; Smith, Colin ; Miles, Gareth B. ; Hardingham, Giles E. ; Wyllie, David J.A. ; Chandran, Siddharthan. / C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. In: Nature Communications. 2018 ; Vol. 9, No. 1.

Bibtex

@article{9f8b8dc9de344d7aa3373c669b6f9304,
title = "C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity",
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.",
author = "Selvaraj, {Bhuvaneish T.} and Livesey, {Matthew R.} and Chen Zhao and Gregory, {Jenna M.} and James, {Owain T.} and Cleary, {Elaine M.} and Chouhan, {Amit K.} and Gane, {Angus B.} and Perkins, {Emma M.} and Owen Dando and Lillico, {Simon G.} and Lee, {Youn Bok} and Nishimura, {Agnes L.} and Urjana Poreci and Sai Thankamony and Meryll Pray and Vasistha, {Navneet A.} and Dario Magnani and Shyamanga Borooah and Karen Burr and David Story and Alexander McCampbell and Shaw, {Christopher E.} and Kind, {Peter C.} and Aitman, {Timothy J.} and Whitelaw, {C. Bruce A.} and Ian Wilmut and Colin Smith and Miles, {Gareth B.} and Hardingham, {Giles E.} and Wyllie, {David J.A.} and Siddharthan Chandran",
note = "Funding Information: 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-Seq raw 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). Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-017-02729-0",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

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 - Funding Information: 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-Seq raw 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). Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

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 - Journal article

C2 - 29367641

AN - SCOPUS:85041044335

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 347

ER -

ID: 282253339