Abstract
Base excision repair is the only DNA repair pathway active in both nuclei and mitochondria and is considered the major DNA repair pathway in neurons. The base excision repair enzyme Endonuclease III-like protein 1 (NTHL1) is a bifunctional glycosylase that mainly excises oxidized pyrimidines from DNA. In Caenorhabditis elegans, genetic perturbation of the NTHL1 orthologue leads to a mitohormetic response that protects dopaminergic neurons from oxidative stress (SenGupta et al., 2021). Similarly, in human cells, genetic NTHL1-perturbation prevents accumulation of toxic DNA repair intermediates and improves mitochondrial function (Hubers et al., 2024).
Here, we hypothesize that pharmacologic NTHL1 perturbation could confer similar resistance against oxidative stress, and here we target NTHL1 using two different potential therapeutic modalities:
Antisense oligonucleotides (ASOs) are short, synthetic single-stranded nucleic acids that bind complementary RNA to modulate gene expression and can be delivered directly to the central nervous system with excellent selectivity and pharmacokinetic stability over several months (Crooke et al 2021).
Small molecule inhibitors are low–molecular-weight organic compounds that bind specific sites on biological targets to block their activity.