Mithormesis promotes dopaminergic neuron health in Base Excision Repair deficient C. elegans

Tanima SenGupta, Konstantinos Palikaras, Henok Kassahun, Alfonso Schiavi, Silvia Maglioni, Lars Eide, Nektarios Tavernarakis, Natascia Ventura, Hilde Nilsen

Oxidative stress and mitochondrial dysfunction are implicated in most common neurodegenerative diseases​. Oxidation of DNA bases is an inevitable consequence of oxidative stress that requires thebase excision repair (BER) pathway for repair. Yet, good experimental evidence to prove that DNA damage and its repair by BER also contributes causally to common, age related neurodegenerative diseases is lacking. To better understand how BER affects aging phenotypes, we study the C. elegans nth-1 mutant, which lacks NTH-1 DNA glycosylase, the only enzyme dedicated to repair of oxidative DNA base damage via the BER pathway. We recently showed that nth-1 mutants have mitochondrial dysfunction characterised by lower mitochondrial DNA copy number, reduced mitochondrial membrane potential, and increased steady-state levels of reactive oxygen species. Consistently, nth-1 mutants express markers of chronic oxidative stress with high basal phosphorylation of MAP-kinases (MAPK) in the germline. Here, we will present new data that suggest that mithormesis protects dopaminergic neurons from age-related degeneration.