Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons
Abstract Disrupted axonal transport and astrocyte dysfunction are implicated in amyotrophic lateral sclerosis (ALS). Here we show these processes are linked—human-induced pluripotent stem-cell-derived astrocytes carrying the C9ORF72 mutation disrupt mitochondrial axonal transport and mitochondrial function in cocultured motor neurons (MNs). Conversely, isogenic gene-corrected astrocytes or boosting astrocytic mitochondrial bioenergetics rescue axonal mitochondrial transport deficits in C9ORF72 MNs. Our results delineate a non-cell-autonomous role for astrocytes in regulating mitochondrial transport along axons in ALS models.
Authors
- David Villarroel‐Campos (ORCID: https://orcid.org/0000-0003-4250-7216)
- Giles E. Hardingham (ORCID: https://orcid.org/0000-0002-7629-5314)
- Daniel Y. H. Soong (ORCID: https://orcid.org/0000-0003-0413-2820)
- Zoeb Jiwaji (ORCID: https://orcid.org/0000-0002-3129-1168)
- Maria Stavrou (ORCID: https://orcid.org/0000-0002-6074-5050)
- Owen Robert Dando (ORCID: https://orcid.org/0000-0002-6269-6408)
- Bhuvaneish Thangaraj Selvaraj (ORCID: https://orcid.org/0000-0001-7299-0910)
- Siddharthan Chandran (ORCID: https://orcid.org/0000-0001-6827-1593)
- Jyoti Nanda (ORCID: https://orcid.org/0000-0002-3547-6266)
- Giampietro Schiavo (ORCID: https://orcid.org/0000-0002-4319-8745)
- Áine Bríd Heffernan (ORCID: https://orcid.org/0000-0002-4991-3949)
- Burr Karen
- Alya Masoud Abdelhafid (ORCID: https://orcid.org/0009-0006-8917-2387)
- Justyna Cholewa-Waclaw
- David Story
- Roderick N. Carter
Institutions
- UK Dementia Research Institute (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- UCL Queen Square Institute of Neurology (GB)
- Euan MacDonald Centre for Motor Neuron Disease Research (GB)
- University College London (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-10-07
- DOI
- https://doi.org/10.1038/s41593-026-02464-0
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00