Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (9): 4253-4254.doi: 10.4103/NRR.NRR-D-25-01831

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Microglia in C9orf72–associated amyotrophic lateral sclerosis: More or less active?

Björn F. Vahsen*, R. Jeroen Pasterkamp*   

  1. Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK (Vahsen BF)
    Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, UK (Vahsen BF)
    Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands (Pasterkamp RJ)
  • Online:2026-09-15 Published:2026-05-12
  • Contact: Björn F. Vahsen, MD, DPhil, bjorn.vahsen@ndcn.ox.ac.uk; R. Jeroen Pasterkamp, PhD, r.j.pasterkamp@umcutrecht.nl.
  • Supported by:
    BFV is funded by the University of Oxford Medical Sciences Division (Reference 0017772) and the Motor Neurone Disease Association Lady Edith Wolfson Junior Non-Clinical Fellowship (Vahsen/Oct25/2553-799). RJP is funded by Stichting ALS Nederland (TOTALS, ALS-on-a-chip, ATAXALS, MUSALS, GoALS), the ERANet for Research on Rare Diseases (E-rare-3: MAXOMOD and INTEGRALS), the ALS CURE project, Alzheimer Nederland and the EU Joint Program for Neurodegenerative Diseases (JPND; TRIAGE).

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Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron (MN) loss and muscle wasting, ultimately leading to death due to respiratory failure. A hexanucleotide (GGGGCC) repeat expansion (HRE) in C9orf72 is the most common genetic cause of ALS (C9-ALS) and frontotemporal dementia. C9orf72 HRE causes ALS through different mechanisms, which include reduced C9orf72 expression, the generation of RNA foci and dipeptide repeat proteins (DPRs), and TAR DNA-binding protein 43 (TDP-43) pathology. A large body of experimental work supports a role for microglial changes in C9-ALS. For example, human post-mortem analyses show microglial tissue infiltration, C9orf72 is strongly expressed in microglia, and loss of C9orf72 leads to lysosomal accumulation and altered pro-inflammatory responses in mice. Furthermore, recent single-cell transcriptomic analysis of human C9-ALS microglia reports an impaired transition of microglia towards a reactive cell state, which is supported by observations in C9-ALS organoid-derived microglia (oMG).