Loss of DNA glycosylases improves health and cognitive function in a C. elegans model of human tauopathy

Vinod Tiwari, Elisabeth Buvarp, Fivos Borbolis, Chandrakala Puligilla, Deborah L. Croteau, Konstantinos Palikaras, Vilhelm A. Bohr*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

1 Citation (Scopus)

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder representing a major burden on families and society. Some of the main pathological hallmarks of AD are the accumulation of amyloid plaques (Aβ) and tau neurofibrillary tangles. However, it is still unclear how Aβ and tau aggregates promote specific phenotypic outcomes and lead to excessive oxidative DNA damage, neuronal cell death and eventually to loss of memory. Here we utilized a Caenorhabditis elegans (C. elegans) model of human tauopathy to investigate the role of DNA glycosylases in disease development and progression. Transgenic nematodes expressing a pro-aggregate form of tau displayed altered mitochondrial content, decreased lifespan, and cognitive dysfunction. Genetic ablation of either of the two DNA glycosylases found in C. elegans, NTH-1 and UNG-1, improved mitochondrial function, lifespan, and memory impairment. NTH-1 depletion resulted in a dramatic increase of differentially expressed genes, which was not apparent in UNG-1 deficient nematodes. Our findings clearly show that in addition to its enzymatic activity, NTH-1 has non-canonical functions highlighting its modulation as a potential therapeutic intervention to tackle tau-mediated pathology.

Original languageEnglish
JournalNucleic Acids Research
Volume52
Issue number18
Pages (from-to)10965-10985
Number of pages21
ISSN0305-1048
DOIs
Publication statusPublished - 2024

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© 2024 Published by Oxford University Press on behalf of Nucleic Acids Research.

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