Neuronal somatic mutations are increased in multiple sclerosis lesions

Neuroinflammation underpins neurodegeneration and clinical progression in multiple sclerosis (MS), but knowledge of processes linking these disease mechanisms remains incomplete. Here we investigated somatic single-nucleotide variants (sSNVs) in the genomes of 106 single neurons from post-mortem brain tissue of ten MS cases and 16 controls to determine whether somatic mutagenesis is involved. We observed an increase of 43.9 sSNVs per year in neurons from chronic MS lesions, a 2.5 times faster rate than in neurons from normal-appearing MS and control tissues. This difference was equivalent to 1,291 excess sSNVs in lesion neurons at 70 years of age compared to controls. We performed mutational signature analysis to investigate mechanisms underlying neuronal sSNVs and identified a signature characteristic of lesions with a strong, age-associated contribution to sSNV counts. This research suggests that neuroinflammation is mutagenic in the MS brain, potentially contributing to disease progression.