Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p=2.35×10⁻¹⁰), that correlated with single-strand breaks in genomic DNA. Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.