Unravelling the role of G-quadruplex structures in brain ageing and neurodegeneration

The increasing incidence of neurodegenerative disorders is posing a significant threat to the NHS and public health services world-wide. Epigenetic regulation has emerged as a critical player in ageing of model organisms and because of its role in integrating environmental stimuli into the genome, represents a therapeutically tractable player in brain ageing and neurodegeneration. Studies from Nativio et al. (Nat. Neuro 2018, Nat. Genet. 2020) have revealed that different epigenetic modifications are differently associated with healthy ageing and Alzheimer's, driving distinct functional pathways. The Di Antonio group has recently demonstrated that the formation of DNA secondary structures known as G-quadruplex (G4) is linked to neurodegeneration (Nat. Commun. 2023) and that the mutation of key proteins that resolve G4s leads to accelerated ageing (J. Am. Chem. Soc. 2021). In this project, we propose to leverage this knowledge to systematically investigate the role of G4-formation in ageing neuron models that are established in the Nativio's group. To achieve this, we plan to combine genome-wide mapping strategies to assess the changes in G4-distribution in ageing neurons with the development of chemical-biology probes to disrupt G4-structures and assess their potential as anti-ageing targets. We anticipate that this project will lead to the identification of G4s that could be targeted to prevent epigenetic dysregulation associated with neurodegeneration.