The implications of neural DNA damage in neurodegeneration

Cells respond to DNA damage by pausing the cell cycle and mounting repair processes. High levels of damage or non-repairable damage can trigger apoptosis. These responses to DNA damage help to reduce the risk of damaged chromosomes or mutations being passed to daughter cells and the risk of cancer. Double-stand breaks to chromosomes are the most deleterious type of DNA damage. They are repaired by the error-prone process of non-homologous end-joining during the G1 phase of the cell-cycle. Additionally, homologous recombination can be employed during M- and S-phases using the sister chromatid as a template to repair the break. In post-mitotic, non-cycling neurons, homologous recombination is not available so double-strand breaks are repaired by non-homologous end-joining.

Double-strand breaks (DSBs) are generated in neurons during normal physiological activity. In mice placed in a novel environment DSBs form but are rapidly repaired, potentially due to upregulation of metabolic activity during exploration of the new environment. However, in disease scenarios, DSBs form to excess and are not completely repaired. DNA damage is also likely to accumulate in neurons during healthy ageing. The consequence is chronic activation of the DNA damage response. We have demonstrated that attenuating the DNA damage response can reduce neuropathology and support neural function multiple different models of neuropathology and in both invertebrate and vertebrate models. This argues that chronic activation of the DNA damage responses in the ageing brain may be contribute to declining neural health with age, and to the neuropathology of neurodegenerative diseases.

This project aims to understand why neurons respond to DNA damage in the way they do. What occurs in neurons when the DNA damage response is activated that leads to impacts on neural health and causes neural dysfunction? Using Drosophila, we will aim to identify the cellular events occurring downstream of activation of the DNA damage response and to identify which components of the DNA damage responses are important for neural health.