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Helping the brain help itself: the purine salvage pathway and the restoration of ATP in ageing neurones and glial cells

Principal Supervisor: Professor Bruno Frenguelli - School of Life Sciences

Co-supervisor: Dr Magnus Richardson - Systems Biology

PhD project title: Helping the brain help itself: the purine salvage pathway and the restoration of ATP in ageing neurones and glial cells

University of Registration: Warwick

Project outline:

The brain utilises the purine salvage pathway to replenish its pool of adenine nucleotides, one of which is ATP – the universal energy currency. However this leaves the brain vulnerable to conditions causing ATP depletion, such as ischemia and trauma as ATP metabolites and substrates for the purine salvage pathway, such as adenosine and hypoxanthine, are lost from the brain during such conditions.

We have shown that it is possible to restore ATP levels in brain tissue using a simple combination of chemicals – ribose and adenine (RibAde). This also results in greater release of adenosine during physiological and pathological stimuli. Given that adenosine is a neuroprotective agent and powerful modulator of neuronal function, the increased release of adenosine has important implications for the brain.

We now wish to extend our previous observations to better appreciate the physiological implications of improving cellular ATP, to begin to establish whether neurones or astrocytes are the primary beneficiaries of RibAde-enhanced cellular ATP, to establish which cell type is the source of the increased adenosine release we observe, and to determine if similar processes occur across the lifespan in mammals.

This project will involve a range of neuropharmacological, microelectrode biosensing, electrophysiological, primary cell culture and imaging techniques to address fundamental issues regarding the way in which the mammalian brain makes and uses arguably the most fundamental of all molecules, ATP.

References:

  1. zur Nedden S, Doney AS, Frenguelli BG. (2014) Modulation of intracellular ATP determines adenosine release and functional outcome in response to metabolic stress in rat hippocampal slices and cerebellar granule cells. J Neurochem. 128: 111-24
  2. zur Nedden S, Hawley S, Pentland N, Hardie DG, Doney AS, Frenguelli BG (2011). Intracellular ATP influences synaptic plasticity in area CA1 of rat hippocampus via metabolism to adenosine and activity-dependent activation of adenosine A1 receptors. J Neurosci. 31: 6221-34

BBSRC Strategic Research Priority: World class bioscience - Neuroscience

Techniques that will be undertaken during the project:

  • Primary neuronal culture and hippocampal slice culture
  • Cellular confocal and multi-photon imaging
  • Electrophysiology
  • Microelectrode biosensors
  • Quantitative biology

Contact: Professor Bruno Frenguelli, University of Warwick