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C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9

Author

Listed:
  • Björn F. Vahsen

    (University of Oxford, John Radcliffe Hospital
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Sumedha Nalluru

    (University of Oxford, John Radcliffe Hospital)

  • Georgia R. Morgan

    (University of Oxford, John Radcliffe Hospital)

  • Lucy Farrimond

    (University of Oxford, John Radcliffe Hospital
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Emily Carroll

    (University of Oxford, John Radcliffe Hospital
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Yinyan Xu

    (University of Oxford, John Radcliffe Hospital
    University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford)

  • Kaitlyn M. L. Cramb

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Benazir Amein

    (University of Oxford, John Radcliffe Hospital)

  • Jakub Scaber

    (University of Oxford, John Radcliffe Hospital
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Antigoni Katsikoudi

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Ana Candalija

    (University of Oxford, John Radcliffe Hospital)

  • Mireia Carcolé

    (UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology)

  • Ruxandra Dafinca

    (University of Oxford, John Radcliffe Hospital
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Adrian M. Isaacs

    (UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology)

  • Richard Wade-Martins

    (University of Oxford, Dorothy Crowfoot Hodgkin Building
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Elizabeth Gray

    (University of Oxford, John Radcliffe Hospital)

  • Martin R. Turner

    (University of Oxford, John Radcliffe Hospital)

  • Sally A. Cowley

    (University of Oxford)

  • Kevin Talbot

    (University of Oxford, John Radcliffe Hospital
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.

Suggested Citation

  • Björn F. Vahsen & Sumedha Nalluru & Georgia R. Morgan & Lucy Farrimond & Emily Carroll & Yinyan Xu & Kaitlyn M. L. Cramb & Benazir Amein & Jakub Scaber & Antigoni Katsikoudi & Ana Candalija & Mireia C, 2023. "C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41603-0
    DOI: 10.1038/s41467-023-41603-0
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    References listed on IDEAS

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    1. Madelyn E. McCauley & Jacqueline Gire O’Rourke & Alberto Yáñez & Janet L. Markman & Ritchie Ho & Xinchen Wang & Shuang Chen & Deepti Lall & Mengyao Jin & A. K. M. G. Muhammad & Shaughn Bell & Jesse La, 2020. "C9orf72 in myeloid cells suppresses STING-induced inflammation," Nature, Nature, vol. 585(7823), pages 96-101, September.
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    Cited by:

    1. Zhefan Stephen Chen & Shaohong Isaac Peng & Lok I Leong & Terence Gall-Duncan & Nathan Siu Jun Wong & Tsz Ho Li & Xiao Lin & Yuming Wei & Alex Chun Koon & Junzhe Huang & Jacquelyne Ka-Li Sun & Clinton, 2025. "Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5," Nature Communications, Nature, vol. 16(1), pages 1-18, December.

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