2025/03/05 by Zinan Zhou, Lovelace J. Luquette, Guanlan Dong +18 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Genetics and Neurodevelopmental Disorders #Mitochondrial Function and Pathology #Amyotrophic Lateral Sclerosis Research
paper · doi:10.1101/2025.03.03.641186
SUMMARY Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s 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.