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 L 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 L Nishimura, Urjana Poreci, Sai Thankamony, Meryll Pray, Navneet A Vasistha, Dario Magnani, Shyamanga Borooah, Karen BurrDavid 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

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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
Pages (from-to)	347
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02729-0
Publication status	Published - 24 Jan 2018

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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

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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.",

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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 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",

year = "2018",

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day = "24",

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

language = "English",

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

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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

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.

KW - Journal Article

U2 - 10.1038/s41467-017-02729-0

DO - 10.1038/s41467-017-02729-0

M3 - Article

C2 - 29367641

SN - 2041-1723

VL - 9

SP - 347

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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