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

Bhuvaneish  Thangaraj Selvaraj; Matthew  Livesey; Chen  Zhao; Jenna  Gregory; Owain   James; Elaine   Cleary; Amit Kumar Chouhan; Angus   Gane; Emma   Perkins; Owen   Dando; Simon   Lillico; Youn-Bok   Lee; Agnes   Nishimura; Urjana   Poreci; Sai   Thankamony; Meryll   Pray; Navneet   Vasistha; Dario   Magnani; Shyamanga   Borooah; Karen   Burr; David   Story; Alexander   McCampbell; Christopher   Shaw; Peter   Kind; Timothy J. Aitman; Bruce   Whitelaw; Ian   Wilmut; Colin   Smith; Gareth B. Miles; Giles   Hardingham; David   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 Thangaraj Selvaraj , Matthew Livesey , Chen Zhao , Jenna Gregory , Owain James, Elaine Cleary, Amit Kumar Chouhan, Angus Gane, Emma Perkins, Owen Dando, Simon Lillico, Youn-Bok Lee, Agnes Nishimura, Urjana Poreci, Sai Thankamony, Meryll Pray, Navneet Vasistha, Dario Magnani, Shyamanga Borooah, Karen BurrDavid Story, Alexander McCampbell, Christopher Shaw, Peter Kind, Timothy J. Aitman, Bruce Whitelaw, Ian Wilmut, Colin Smith, Gareth B. Miles, Giles Hardingham, David 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 neuron (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
Number of pages	14
Journal	Nature Communications
Volume	9
Early online date	24 Jan 2018
DOIs	https://doi.org/10.1038/s41467-017-02729-0
Publication status	E-pub ahead of print - 24 Jan 2018

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Final published version, 5.31 MBLicence: CC BY

MNDA Studentship: Deciphering mechanisms underlying the dysfunction of motoneorons derived from ALS patient iPSCs
Miles, G. B. (PI)
27/09/15 → 26/09/18
Project: Studentship

Gareth Brian Miles
- gbm4st-andrews.acuk
- School of Psychology and Neuroscience - Professor of Neuroscience
- Sir James Mackenzie Institute for Early Diagnosis
- Centre for Biophotonics
- Institute of Behavioural and Neural Sciences - Director
Person: Academic

Cite this

Thangaraj Selvaraj , B., Livesey , M., Zhao , C., Gregory , J., James, O., Cleary, E., Chouhan, A. K., Gane, A., Perkins, E., Dando, O., Lillico, S., Lee, Y.-B., Nishimura, A., Poreci, U., Thankamony, S., Pray, M., Vasistha, N., 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. Advance online publication. https://doi.org/10.1038/s41467-017-02729-0

@article{705fda59644f4d57958094959caf7359,

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 neuron (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 = "{Thangaraj Selvaraj}, Bhuvaneish and Matthew Livesey and Chen Zhao and Jenna Gregory and Owain James and Elaine Cleary and Chouhan, {Amit Kumar} and Angus Gane and Emma Perkins and Owen Dando and Simon Lillico and Youn-Bok Lee and Agnes Nishimura and Urjana Poreci and Sai Thankamony and Meryll Pray and Navneet Vasistha and Dario Magnani and Shyamanga Borooah and Karen Burr and David Story and Alexander McCampbell and Christopher Shaw and Peter Kind and Aitman, {Timothy J.} and Bruce Whitelaw and Ian Wilmut and Colin Smith and Miles, {Gareth B.} and Giles Hardingham and David Wyllie and Siddharthan Chandran",

note = "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).",

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

language = "English",

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Thangaraj Selvaraj , B, Livesey , M, Zhao , C, Gregory , J, James, O, Cleary, E, Chouhan, AK, Gane, A, Perkins, E, Dando, O, Lillico, S, Lee, Y-B, Nishimura, A, Poreci, U, Thankamony, S, Pray, M, Vasistha, N, Magnani, D, Borooah, S, Burr, K, Story, D, McCampbell, A, Shaw, C, Kind, P, Aitman, TJ, Whitelaw, B, Wilmut, I, Smith, C, Miles, GB, Hardingham, G, Wyllie, D & 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 - Thangaraj Selvaraj , Bhuvaneish

AU - Livesey , Matthew

AU - Zhao , Chen

AU - Gregory , Jenna

AU - James, Owain

AU - Cleary, Elaine

AU - Chouhan, Amit Kumar

AU - Gane, Angus

AU - Perkins, Emma

AU - Dando, Owen

AU - Lillico, Simon

AU - Lee, Youn-Bok

AU - Nishimura, Agnes

AU - Poreci, Urjana

AU - Thankamony, Sai

AU - Pray, Meryll

AU - Vasistha, Navneet

AU - Magnani, Dario

AU - Borooah, Shyamanga

AU - Burr, Karen

AU - Story, David

AU - McCampbell, Alexander

AU - Shaw, Christopher

AU - Kind, Peter

AU - Aitman, Timothy J.

AU - Whitelaw, Bruce

AU - Wilmut, Ian

AU - Smith, Colin

AU - Miles, Gareth B.

AU - Hardingham, Giles

AU - Wyllie, David

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-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).

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 neuron (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 neuron (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

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

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MNDA Studentship: Deciphering mechanisms underlying the dysfunction of motoneorons derived from ALS patient iPSCs

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Gareth Brian Miles

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