Cellular rejuvenation protects neurons from inflammation-mediated cell death
In multiple sclerosis (MS), inflammation of the central nervous system results in demyelination, neuroaxonal injury, and cell death. However, the molecular signals responsible for injury and cell death in neurons are not fully characterized. Here, we profile the transcriptome of retinal ganglion cells (RGCs) in experimental autoimmune encephalomyelitis (EAE) mice. Pathway analysis identifies a transcriptional signature reminiscent of aged RGCs with some senescent features, with a comparable signature present in neurons from patients with MS. This is supported by immunostaining demonstrating alterations to the nuclear envelope, modifications in chromatin marks, and accumulation of DNA damage. Transduction of RGCs with an Oct4-Sox2-Klf4 adeno-associated virus (AAV) to rejuvenate the transcriptome enhances RGC survival in EAE and improves visual acuity. Collectively, these data reveal an aging-like phenotype in neurons under pathological neuroinflammation and support the possibility that rejuvenation therapies or senotherapeutic agents could offer a direct avenue for neuroprotection in neuroimmune disorders.
Authors
- Kali Heale
- Elizabeth M.-L. Hua (ORCID: https://orcid.org/0000-0002-7403-6511)
- David Gosselin (ORCID: https://orcid.org/0000-0001-5327-2868)
- Abdulshakour Mohammadnia (ORCID: https://orcid.org/0000-0003-1982-3958)
- David Sinclair (ORCID: https://orcid.org/0000-0002-9936-436X)
- Alyson E. Fournier (ORCID: https://orcid.org/0000-0002-1859-7015)
- Stéphanie Zandee (ORCID: https://orcid.org/0000-0003-0812-676X)
- Matthew A Hintermayer (ORCID: https://orcid.org/0000-0003-0328-7089)
- Yuancheng Ryan Lu (ORCID: https://orcid.org/0000-0002-5982-3963)
- Alexandre Prat (ORCID: https://orcid.org/0000-0001-6188-0580)
- Jo Anne Stratton (ORCID: https://orcid.org/0000-0002-1205-1353)
- Aliyah Zaman (ORCID: https://orcid.org/0000-0002-9926-3227)
- Adam M.R. Groh (ORCID: https://orcid.org/0000-0002-5878-0973)
- Sienna Drake (ORCID: https://orcid.org/0000-0001-7537-3520)
- Christine Gianfelice
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Harvard University (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- Université Laval (CA)
- McGill University (CA)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115298
- Citations
- 14
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 11.16
Funders
- Foundation for the National Institutes of Health
- National Multiple Sclerosis Society
- Glenn Foundation for Medical Research
- Multiple Sclerosis Society of Canada
- Fondation pour la Recherche Médicale
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute on Aging
- Institute of Neurosciences, Mental Health and Addiction