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Investigating the neuronal response to DNA damage: implications for neurodegeneration

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

Co-supervisor: Prof. Charalambos Kyriacou, Department of Genetics and Genome Biology, University of Leicester

PhD project title: Investigating the neuronal response to DNA damage: implications for neurodegeneration

University of Registration: University of Birmingham

 

Project outline:

The ability to recognise damaged DNA and respond to it is a fundamental property of cells. Cells respond to damage by halting the cell cycle and initiating repair and, if damage is extensive, entering a senescent state or triggering apoptosis. Together, the DNA damage responses function as defence against cancer. Post-mitotic neurons in the CNS respond to DNA damage in a similar manner to actively cycling cells but these responses may not be appropriate: neurons can’t be replaced if apoptosis is triggered and senescent neurons are potentially toxic to neighbours.

It is becoming clear that the most toxic form of DNA damage – double-strand breaks – accumulates in many forms of neurodegeneration. This project asks a series of questions about why neurons respond to DNA damage in the way they do and whether the response is inappropriate and actually contributes to neural diseases, especially neurodegeneration. The questions are based on recent discoveries in the Tuxworth lab and Kyriacou laboratories that suppressing the DNA damage response in neurons can be beneficial in models of neurodegeneration and prevent loss of neurons. For instance: what happens if detection of DNA damage is inhibited? Can neurons actually tolerate DNA damage in non-transcribed regions, given they are not trying to replicate the DNA? What happens if actively-dividing glia are inhibited from responding to damage? Does damage to mitochondrial DNA elicit a similar effect in neurons to nuclear damage? And can modifying the responses of neurons protect neurons from senescent and apoptosis in vivo?

The project will primarily use Drosophila models engineered to exhibit aspects of human neurological diseases and use the genetic tools of Drosophila to manipulate the DNA damage response in vivo. The student will then and ask what happens to the neurobiology of the flies using activity tests; behavioural tests, including circadian analysis and memory tests; histology and immunofluorescent microscopy to analyse apoptosis, senescence and cell-cycle within the CNS. The molecular changes occurring in neurons will be studied primarily in vitro. The student will used cultured human neuroblastoma cells and iPS-derived neurons and glia derived from neurodegeneration patients to assess changes to the DNA damage response and more widely to the proteome and transcriptome. A live-cell FRET-sensor for the DNA damage response will be constructed and tested in vitro to aid quantification and visualisation of the response.

The student will benefit from the combined expertise of two Drosophila groups at Birmingham and Leicester plus the support of a wider community of Drosophila groups at the two Universities. The student will be based primarily in Birmingham in the Tuxworth group where the majority of the Drosophila and cell-based studies will be performed with the more advanced behavioural studies taking place in Leicester in the Kyriacou group. The Tuxworth group is based in the College of Medical and Dental Sciences alongside world-leading colleagues studying the DNA damage response and alongside colleagues routinely using disease-related iPS cells models.

 

BBSRC Strategic Research Priority: Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  • Drosophila genetics
  • Cell biology
  • Neurobiology
  • Behavioural analysis
  • Circadian analysis
  • Proteomics
  • Transcriptomics


Contact: Dr Richard Tuxworth, Institute of Cancer and Genomic Sciences