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

Abstract

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimers disease (AD) represent two major categories of neurodegenerative disorders--TDP-43 and tau proteinopathies--for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons--but only 2% of control neurons--resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid Approach to DNA Adduct Recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represents a mechanism shared by both TDP-43 and tau neurodegeneration.