DNA Damage Response in Huntington’s Disease and Naked Mole Rat Brain Ageing

This thesis investigates the molecular mechanisms underlying healthy brain ageing in the exceptionally long-lived naked mole rat (NMR) and the role of the DNA damage response in the pathogenesis of Huntington's disease (HD). Multi-omic analyses of NMR brain ageing revealed a lack of a canonical ageing signature in the NMR cortex, with no observed increase in inflammation, DNA damage, or cellular senescence. Single-cell sequencing uncovered cell type-specific changes, with GABAergic neurons and astrocytes showing the most pronounced age-related alterations. Investigating the role of DNA damage in HD, the thesis demonstrated that HD cells display increased sensitivity to genotoxic stress and impairments in specific DNA repair pathways. CRISPR screens identified novel genes and pathways that modulate the cellular response to DNA damage in the context of expanded HTT. This thesis also investigated other DDR genes involved with repeat expansion in HD and identified potential modifiers of CAG expansion such as MBD4, PMS2, and RNASEH2A. Several hits from this arrayed CRISPR screen for modifiers of CAG repeat expansion converged on the regulation of R-loops, suggesting that these DNA-RNA hybrid structures may contribute to CAG repeat instability and genomic instability in HD. Integration of these findings highlights the central importance of genomic stability and cellular homeostasis in brain health and disease. The NMR's remarkable resistance to age- related brain pathology underscores the significance of maintaining an anti-inflammatory homeostasis and genomic integrity for healthy brain ageing. Conversely, the increased DNA damage sensitivity and repair deficits in HD cells demonstrate how disruption of these key cellular pathways can lead to neurodegeneration. The insights gained from this work could inform the development of interventions to promote healthy brain ageing and combat age- related neurodegeneration.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Ungerleider, Kyra

Advisor dc:contributor.advisor

• Balmus, Gabriel

• ageing
• DNA damage
• Huntington's
• naked mole rat
• neurodegeneration

Licence

• https://www.repository.cam.ac.uk/bitstreams/11548457-833e-4a10-b9e0-590540e69857/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.112802

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/374929