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Title: P53 signalling in microglia : implications for neurodegeneration
Author: Jebelli, J. D.
ISNI:       0000 0004 5363 4058
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Emerging evidence suggests that p53, a tumour suppressor protein thought to be primarily involved in cancer biology, also coordinates a diverse variety of novel functions in the CNS including mediating pathways underlying neurodegenerative disease pathogenesis. Moreover, an evolving concept in cell and molecular neuroscience is that glial cells may be far more fundamental to disease progression than previously thought, which may occur via a non-cell-autonomous mechanism that is also heavily dependent on p53 activities. As a crucial hub connecting many intracellular control pathways, including cell-cycle control and apoptosis, p53 is ideally placed to coordinate the cellular response to a range of stresses. The data reported in this thesis demonstrates crucial roles for p53 in mediating microglial activation. This behavior occurs via a transcription-dependent mechanism, with the subsequent inhibition of microglial p53 leading to reductions in neuronal cell death. Furthermore, the loss of synapses represents a key early feature in numerous neurological disorders, with mounting evidence implicating microglia as causal agents in this process, via a phenomenon known as synaptic stripping. We reveal evidence suggesting that microglial p53 is detrimental to synaptic properties, prior to any visible signs of neuronal cell death, and that such behaviour correlates with changes in neuronal exocytosis, microglial cytokine production, and phosphorylated p53 activity in microglia. Although neurodegenerative diseases each display a distinct and diverse molecular pathology, the multimodal capacity of the p53 system to orchestrate apoptosis and microglial cell behaviour highlights this protein as a potential unifying target for therapeutic intervention.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available