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Defining a functional link between constitutive and transcriptional defences to oxidative stress in neurons


Project Description

The activator protein-1 (AP-1) transcription factor is comprised of a Fos and Jun dimer and is the primary mediator of protective and pro-apoptotic responses of neurons to reactive oxygen species (ROS). ROS are a major factor in neurodegeneration causing damage to lipids proteins and DNA, but at low levels also act as physiological signals of neuronal activity. Regulation and activation of AP-1 in neurons in response to ROS at both physiological and pathological levels is poorly understood. We have identified a ROS-dependent binding of AP-1 to GTP-cyclohydrolase 1 (GTPCH1). GTPCH1 catalyses the rate limiting step in the synthesis of the ROS scavenger tetrahydrobiopterin (BH4). GTPCH1 activity is inhibited by increasing levels of BH4 production. We find that AP-1 binds to GTPCH1 in a ROS and BH4 dependent manner linking constitutive neuronal antioxidant levels (BH4) to an adaptive protection response (AP-1) in a rheostat-type mechanism. We now aim to characterise the structural and biophysical interactions between the components of this critical protective mechanism for neurons. As an initial step, we have generated for the first time, soluble recombinant heterodimers of Fos/Jun. A major first step in this project is to determine the structure of this critical transcription factor. This will be followed by the determination of the parameters of interaction between AP-1, BH4 and GTPCH1 using X-ray crystallography and cryo-electron microscopy. This work will characterise an important ROS protective mechanism for neurons.

Funding Notes

This is a BBSRC WR DTP studentship fully-funded for 4 years and covers: (i) a tax-free stipend at the standard Research Council rate (around £15,000 per year) (ii) research costs, and (iii) tuition fees at the UK/EU rate. The studentship is available to UK and EU students who meet the UK residency requirement (to have been residing in the UK for at least 3 years continuously prior to the start of the PhD).

References

ENTRY REQUIREMENTS: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.

How good is research at University of York in Biological Sciences?

FTE Category A staff submitted: 44.37

Research output data provided by the Research Excellence Framework (REF)

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