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

Author

Listed:
  • Bhuvaneish T. Selvaraj

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Matthew R. Livesey

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Chen Zhao

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Jenna M. Gregory

    (University of Edinburgh
    University of Edinburgh)

  • Owain T. James

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Elaine M. Cleary

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Amit K. Chouhan

    (University of Edinburgh
    University of St Andrews)

  • Angus B. Gane

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Emma M. Perkins

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Owen Dando

    (University of Edinburgh
    inStem)

  • Simon G. Lillico

    (University of Edinburgh)

  • Youn-Bok Lee

    (King’s College London)

  • Agnes L. Nishimura

    (King’s College London)

  • Urjana Poreci

    (Biogen)

  • Sai Thankamony

    (Biogen)

  • Meryll Pray

    (Biogen)

  • Navneet A. Vasistha

    (University of Edinburgh
    University of Edinburgh
    inStem)

  • Dario Magnani

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Shyamanga Borooah

    (University of Edinburgh)

  • Karen Burr

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • David Story

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Alexander McCampbell

    (Biogen)

  • Christopher E. Shaw

    (King’s College London)

  • Peter C. Kind

    (University of Edinburgh
    inStem)

  • Timothy J. Aitman

    (University of Edinburgh)

  • C. Bruce A. Whitelaw

    (University of Edinburgh)

  • Ian Wilmut

    (University of Edinburgh)

  • Colin Smith

    (University of Edinburgh
    University of Edinburgh)

  • Gareth B. Miles

    (University of Edinburgh
    University of St Andrews)

  • Giles E. Hardingham

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • David J. A. Wyllie

    (University of Edinburgh
    University of Edinburgh
    inStem)

  • Siddharthan Chandran

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh
    inStem)

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.

Suggested Citation

  • 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 & You, 2018. "C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02729-0
    DOI: 10.1038/s41467-017-02729-0
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