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

Bhuvaneish T. Selvaraj; Matthew R. Livesey; Chen Zhao; Jenna M. Gregory; Owain T. James; Elaine M. Cleary; Amit K. Chouhan; Angus B. Gane; Emma M. Perkins; Owen Dando; Simon G. Lillico; Youn-bok Lee; Agnes Lumi Nishimura; Urjana  Poreci; Sai  Thankamony; Meryll Pray; Navneet A. Vasistha; Dario Magnani; Shyamanga Borooah; Karen Burr; David Story; Alexander  McCampbell; Christopher E. SHAW; Peter C. Kind; Timothy J. Aitman; C. Bruce A. Whitelaw; Ian Wilmut; Colin Smith; Gareth B. Miles; Giles E. Hardingham; David J. A. Wyllie; Siddharthan Chandran

doi:10.1038/s41467-017-02729-0

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

Bhuvaneish T. Selvaraj
, Matthew R. Livesey
, Chen Zhao
, Jenna M. Gregory
, Owain T. James
, Elaine M. Cleary
, Amit K. Chouhan
, Angus B. Gane
, Emma M. Perkins
, Owen Dando
, Simon G. Lillico
, Youn-bok Lee
, Agnes Lumi Nishimura
, Urjana Poreci
, Sai Thankamony
, Meryll Pray
, Navneet A. Vasistha
, Dario Magnani
, Shyamanga Borooah
, Karen Burr

David Story, Alexander McCampbell, Christopher E. SHAW, Peter C. Kind, Timothy J. Aitman, C. Bruce A. Whitelaw, Ian Wilmut, Colin Smith, Gareth B. Miles, Giles E. Hardingham, David J. A. Wyllie, Siddharthan Chandran

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	347
Journal	Nature Communications
Volume	9
Early online date	24 Jan 2018
DOIs	https://doi.org/10.1038/s41467-017-02729-0
Publication status	Published - 24 Jan 2018

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Future-Proofing the sustainability of the MRC high throughput sequencing hub in Scotland
Blaxter, M. (Principal Investigator)
MRC
1/10/12 → 30/09/14
Project: Research
Ark Genomics
Watson, M. (Principal Investigator), Archibald, A. (Co-investigator) & Burt, D. (Co-investigator)
Biotechnology and Biological Sciences Research Council
1/04/12 → 31/03/17
Project: Research
Receptors, Function and plasticity in human embryonic stem cell-derived neurons.
Ffrench-Constant, C. (Principal Investigator)
UK-based charities
10/01/11 → 9/01/15
Project: Research

Siddharthan Chandran
Person: Academic: Research Active
Simon Lillico
- simon.lillicoroslin.ed.acuk
- Royal (Dick) School of Veterinary Studies - Core Scientist (Research Fellow)
- Edinburgh Imaging
Person: Academic: Research Active
David Wyllie
- School of Neurological and Cardiovascular Sciences - Personal Chair of Ion Channel Physiology and Pharmacology
- Centre for Discovery Brain Sciences - Director
- Euan MacDonald Centre for Motor Neuron Disease Research
- Edinburgh Neuroscience
Person: Academic: Research Active

Cite this

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., 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, Article 347. https://doi.org/10.1038/s41467-017-02729-0

@article{e0be938a10d14396ab114f3226528176,

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 Youn-bok Lee and Nishimura, \{Agnes Lumi\} 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",

year = "2018",

month = jan,

day = "24",

doi = "10.1038/s41467-017-02729-0",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Selvaraj, BT, Livesey, MR, Zhao, C, Gregory, JM, James, OT, Cleary, EM, Chouhan, AK, Gane, AB, Perkins, EM , Dando, O , Lillico, SG, Lee, Y, 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, 347. https://doi.org/10.1038/s41467-017-02729-0

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 Lumi

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

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.

U2 - 10.1038/s41467-017-02729-0

DO - 10.1038/s41467-017-02729-0

M3 - Article

C2 - 29367641

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 347

ER -

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

Abstract

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Projects

Future-Proofing the sustainability of the MRC high throughput sequencing hub in Scotland

Ark Genomics

Receptors, Function and plasticity in human embryonic stem cell-derived neurons.

Profiles

Siddharthan Chandran

Simon Lillico

David Wyllie

Cite this

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