Multiple Sclerosis: New Insights into the Role of Somatic Mutations in Neuronal Damage

A recent study has shed light on the role of somatic mutations in the progression of multiple sclerosis (MS), the most common inflammatory disease of the central nervous system (CNS). The research, published in Nature Neuroscience, investigated somatic single-nucleotide variants (sSNVs) in single neurons from post-mortem brain tissue of MS patients and healthy controls. The findings suggest that neuroinflammation in MS is mutagenic, potentially contributing to disease progression.

What are Somatic Mutations?
Somatic mutations are alterations in the DNA sequence of cells that are acquired after conception. These mutations are not inherited and can occur due to various factors, including aging, environmental exposures, and inflammation. Somatic mutations in neurons have been implicated in neurodegenerative diseases.

Key Findings of the Study
* The study found that neurons from chronic MS lesions had a 2.5 times faster rate of sSNV accumulation compared to neurons from normal-appearing MS tissue and control tissues. This difference was equivalent to 1,291 excess sSNVs in lesion neurons at 70 years of age compared to controls.

* Mutational signature analysis identified a signature characteristic of lesions with a strong, age-associated contribution to sSNV counts.

* MS lesion-resident neurons had excess sSNVs. The rate of increase in MS lesions was estimated as 43.9 sSNVs per year. The mean sSNV count in MS lesion and MS NA tissue is equal at age 35.1 years.

* MS NA tissue neurons also have excess sSNVs compared to control. MS NA tissue had a mean excess of 376.6 sSNVs relative to all controls.

* Five COSMIC signatures were found to have contributions associated with age: SBS5, SBS89, SBS12, SBS88 and SBS30. MS sig 2 contributions to sSNVs revealed a disease association, being elevated by the same amount in MS NA and lesion tissue relative to controls and MS sig 3 had a lesion association, contributing to excess sSNVs in MS lesion versus controls.

Implications for MS Pathophysiology
MS is characterized by focal lesions in the brain and spinal cord, representing inflammation, demyelination, and axonal loss. The study's findings suggest that chronic neuroinflammation in MS induces somatic mutagenesis in CNS-resident cells, potentially driving or contributing to disease progression.

The researchers propose that the presence of an SBS1-like signature in MS tissues may reflect regenerative processes, such as neurogenesis, that occur in response to chronic neuroinflammation to replace damaged or dead neurons. Signatures SBS19 and SBS42 operate in MS lesions and not in control tissue, pointing to lesion-specific mutational processes that are linked to DNA damage caused by environmental exposure to haloalkanes and certain cancer types.

Potential Therapeutic Strategies
The study highlights the need for neuroprotective and regenerative medicines to enhance CNS resilience to neuroinflammation-associated DNA damage. Better knowledge of the molecular processes involved in neuroinflammation and neurodegeneration in MS may enable the development of such therapies, which may be used in combination with disease-modifying therapies to treat both relapsing and progressive forms of MS.

Methods Used
* The researchers obtained frozen tissue blocks from the donor brains of ten MS cases and five controls.

* They used fluorescence-activated nuclei sorting (FANS) to isolate neuronal nuclei.

* Whole-genome amplification (WGA) and whole-genome sequencing (WGS) were performed on single-neuronal nuclei.

* sSNVs were detected in single neurons using SCAN2.

* Mutational signature analysis was performed using MutationalPatterns.

The study provides compelling evidence that somatic mutations play a significant role in the pathophysiology of MS. These findings open new avenues for research and therapeutic development, potentially leading to more effective treatments for this debilitating disease.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Motyer, A., Jackson, S., Yang, B. et al. Neuronal somatic mutations are increased in multiple sclerosis lesions. Nat Neurosci (2025). https://doi.org/10.1038/s41593-025-01895-5