Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.

Recurrent TOP1-mediated neuronal genomic damage occurs in over 60% of neurons across ALS, FTD, and AD, linking mutagenesis to neurodegeneration.

• Why it matters: Understanding the mechanisms of neuronal death in neurodegenerative diseases is crucial for developing targeted therapies, yet these processes remain poorly defined.
• What they did: Single-cell whole-genome sequencing of 469 neurons from affected and control brains identified increased somatic mutations and a mutational signature linked to TOP1 activity, confirmed by RADAR and duplex sequencing.
• The result: The findings reveal that TOP1-associated mutagenesis and genome instability are common mechanisms in TDP-43 and tau proteinopathies, offering new insights into shared disease pathways.