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0This study utilizes single-cell whole-genome sequencing to reveal that neurons in ALS, FTD, and Alzheimer’s disease exhibit significantly elevated levels of somatic mutations compared to healthy brains. Researchers identified a specific mutational signature primarily composed of 2-bp deletions, which serves as a unifying marker of genomic instability across these diverse neurodegenerative conditions. This damage is driven by the aberrant activity of topoisomerase 1 (TOP1), an enzyme that becomes trapped on DNA and causes strand breaks, especially under conditions of oxidative stress. Interestingly, these high mutation burdens were found in both neurons with and without TDP-43 pathology, suggesting that the genetic decay occurs independently of certain classic disease markers. Furthermore, the absence of this specific genomic damage in cerebellar cells highlights a unique vulnerability in the cortical neurons typically ravaged by these disorders. Ultimately, the findings suggest that TOP1-mediated DNA damage represents a shared biological pathway that contributes to the death of neurons in multiple forms of dementia.
References:
Zhou Z, Luquette L J, Dong G, et al. Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders[J]. Cell, 2026.
