Principal Supervisor: Dr. Richard TuxworthLink opens in a new window

Co-supervisor: Prof. Zubair Ahmed

PhD project title: The effect of DNA damage on neural function

University of Registration: University of Birmingham

Project outline:

DNA is constantly damaged by errors in replication, by the action of reactive oxygen species generated as a product of metabolism and by exogenous sources, including radiation and carcinogens. Highly conserved cellular mechanisms exist to repair DNA damage or, should the damage be extensive, to trigger apoptosis so that genome stability is maintained.

 

In the mature nervous system, triggering apoptosis would lead to the permanent loss of neurons since the vast majority are not replaceable. So how do neurons deal with inevitable DNA damage? What happens in situations where DNA damage is accumulating faster than it can be repaired? If neurons don’t die by apoptosis, what effect does chronic activation of the DNA damage responses have for neural function?

 

DNA damage accumulates in neurons during normal ageing and pathologically in most ­– potentially all – neurological diseases, including late-onset neurodegeneration and after acute trauma to the nervous system, such as stroke or spinal injury. Hence, the DNA damage responses are chronically activated in all of these scenarios. Importantly, our previous work has demonstrated that inhibiting DNA damage signalling protects the nervous system and supports recovery in animal models of Alzheimer’s disease and spinal cord injury (Refs. 1-3), indicating that chronic DNA damage signalling does impact adversely on neural function.

 

This project will examine the effects of accumulating DNA damage in the nervous system to help understand its contribution to the decline in nervous system function during normal ageing and the accelerated decline seen in neurological disease. We will ask why neural function is impacted by chronic DNA damage signalling by looking for the changes that occur in neurons downstream of the DNA damage response. Possible changes include the unwinding of heterochromatin, remobilisation of transposable elements, induction of stress responses and alterations to mitochondrial function. There are also likely to be extensive changes in gene expression. Apoptosis is not likely to be a major outcome.

 

The project will use human neuroblastoma cells and Drosophila as the primary in vitro and vivo models, respectively. A promiscuous CRISPR/Cas9 nuclease system will be used to generate multiple DNA breaks. This will be combined with genetic tools in Drosophila to restrict expression to small neural networks that regulate known behavioural tasks, such as fine movement control and sleep regulation. This will allow the effects on neural activity and function to be quantified. Genomic approaches such as ATAC-seq, RNA-seq and long-range sequencing plus the use of genetically-encoded reporters of metabolism will complement the neurobiology studies to give a rounded picture of the effect of DNA damage on the nervous system in ageing and in disease.

 

References:

Tuxworth et al, 2019. Brain comms. https://doi.org/10.1093/braincomms/fcz005

Ahmed and Tuxworth, 2022. Clin. Trans. Med. doi: 10.1002/ctm2.962

Taylor et al, 2022. Science Advances. https://www.science.org/doi/10.1126/sciadv.abq2611

BBSRC Strategic Research Priority: Integrated Understanding of Health - Ageing

Techniques that will be undertaken during the project:

Genetics, Drosophila models, cell biology, molecular biology and cloning, confocal and super-resolution microscopy, behavioural testing, genomics

Contact: Dr. Richard TuxworthLink opens in a new window