Reducing Base Excision Repair Alleviates Tau-Induced Neurotoxicity

Tiwari V, Buvarp E, Borbolis F, Puligilla C, Croteau DL, Palikaras K, Bohr VA. Loss of DNA glycosylases improves health and cognitive function in a C. elegans model of human tauopathy. Nucleic Acids Res 2024;52(18):10965-10985. doi: 10.1093/nar/gkae705.

Background: Alzheimer’s disease (AD) is characterized by amyloid plaques and tau neurofibrillary tangles, leading to oxidative DNA damage and neuronal dysfunction. Base excision repair (BER) is essential for maintaining genomic stability, but dysregulation of DNA glycosylases may contribute to neurodegeneration. Because Caenorhabditis elegans has only two DNA glycosylases, UNG-1 and NTH-1, it provides a simplified model to investigate how BER imbalance influences tau-associated pathology.

Hypothesis: This study hypothesized that genetic ablation of the DNA glycosylases NTH-1 and UNG-1 would mitigate tau-induced toxicity by reducing BER-associated DNA damage, thereby improving health span, mitochondrial function and cognition in C. elegans models of tauopathy.

Methods: The authors used transgenic C. elegans strains expressing aggregation-prone tau (BR5270) or control tau (BR5271), crossed with NTH-1 or UNG-1 mutants. Locomotion was quantified using WormLab, and lifespan, brood size and memory were assessed through established assays. RNA sequencing and immunohistochemistry were used to analyze transcriptional and cellular outcomes.

Results: Loss of NTH-1 or UNG-1 significantly improved lifespan, brood size and memory in tau-expressing worms. NTH-1 deficiency reduced oxidative DNA lesions and TUNEL-positive foci, enhanced mitochondrial membrane potential and extended survival under oxidative and genotoxic stress. RNAseq revealed extensive transcriptional reprogramming in NTH-1 mutants, distinct from UNG-1 deficiency.

Conclusions: These findings demonstrate that reduced BER initiation via DNA glycosylase loss alleviates tau-associated neurotoxicity, likely through decreased DNA damage and improved mitochondrial homeostasis. Modulating NTH-1 activity may thus represent a potential therapeutic strategy for AD.