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Maintaining neuronal health by manipulating DNA damage responses

Principal Supervisor: Dr. Richard Tuxworth - Institute of Cancer and Genomic Sciences

Co-supervisor: Dr. Boris Kysela

PhD project title: Maintaining neuronal health by manipulating DNA damage responses

University of Registration: Birmingham

Project outline:

The earliest pathological events identifiable in all neurodegenerative conditions, whether common late-onset diseases such as dementias or rare inherited early-onset forms, are loss of synapses. Indeed, these and other neuropathological conditions are now often referred to as “synaptopathies”. A similar loss of synapses is also thought likely to underpin the slow decline in cognitive and motor functions that accompany healthy ageing. Despite this, our understanding the molecular mechanisms leading to synapse stabilisation during development and the loss of synapse stability during ageing and neuropathology are poor. This project will focus on one fundamental process in cell biology that our recent findings show can be manipulated to maintain neural function – the responses to DNA damage.

Previous work in our laboratories has discovered that reducing the ability of cells to sense DNA damage protects neurons in various neuropathological conditions, including neurotrauma events such as transection of the spinal cord or crush of the optic nerve and in neurodegeneration including models of Alzheimer’s and Huntingdon’s diseases. It is likely also to affect the normal healthy ageing process. This project will look at the highly conserved DNA damage responses pathways – the same pathways exist from yeast to human – and ask how it interacts with neural behaviour and function and how synapses are affected when it is modulated.

The project will use two complementary models. Firstly, Drosophila will be used to investigate neural health, synapse number and function in vivo, taking advantage of the powerful genetic tools to manipulate DNA damage responses. Synapse number and morphology will be assessed by various microscopy techniques, including light microscopy and EM, by biochemistry and with state-of-the-art genetic labelling techniques currently under development in Drosophila. Functions of the nervous system will be assessed directly by electrophysiology and by quantitating changes in olfactory behaviour and in animal movement. Secondly, a cell and protein biochemistry-based approach including use of nanoparticles will be used to determine the molecular mechanisms that underpin the in vivo responses.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Drosophila genetics
  • CRISPR/Cas9 genome editing
  • Neural physiology
  • Behavioural analysis
  • Electrophysiology
  • Cell culture
  • Protein biochemistry
  • Nanoparticle biochemistry

Contact: Dr Richard Tuxworth, University of Birmingham