Other effects of ethanol metabolism include an interference with one carbon (1-C) pathways, due to a reduction in neuronal S-adenosyl methionine (Sun et al., 2023), a major methyl donor for a broad array of vital cellular processes (Bottiglieri, 2002). The intermediate in metabolizing ethanol, acetaldehyde, also induces DNA crosslinks, triggering a DNA damage response, and this has been observed in neurons (Sun et al., 2023). This is particularly dangerous since neurons are post-mitotic and therefore DNA damage induces alternate DNA repair mechanisms such as mismatch repair (MMR) leading to the recruitment of cell cycle-independent excision-based repair (Kato et al., 2017, SenGupta et al., 2013). The combination of DNA repair stimulation and 1-C pathway depletion leads to neuronal senescence (Sun et al., 2023), which likely contributes to neurodegeneration found in chronic alcohol use.
