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Title: Identification of a new player in human neural stem cell death and survival - Peptidylarginine Deiminase 3
Author: U, K. P.
ISNI:       0000 0004 5363 5990
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Peptidylarginine Deiminases (PADs) modify protein conformation and function by converting protein-bound arginine to citrulline in a calcium-dependent manner. These processes have been shown to be important in the developing nervous system. Ferretti et al in 2011 demonstrated only PAD2 and PAD3 were detected in the developing chick spinal cord. PAD3 is of particular interest due to its expression in neural stem cells (NSCs) and possible involvement in secondary injury responses in chick, a process that involves calcium deregulation. Cl-amidine, a PAD inhibitor has been shown to significantly reduce spinal cord damage. The aims of my project were to investigate the developmental expression of PADs and their possible function in apoptosis in human central nervous system (CNS) as none of these issues were addressed previously. Out of 5 PADs in human only PAD2 and PAD3 were detected in developing CNS. PAD3 transcript decreases while PAD2 increases with development. I also found PAD3 expression in the spinal cord germinal zone, thereby indicating its expression in human NSCs (hNSCs), and then I established hNSC lines from human embryonic CNS and they showed PAD2 and PAD3 expression which were regulated upon differentiation. To investigate PAD3 involvement in apoptosis in human CNS, intracellular calcium was raised in hNSCs to mimic secondary injury responses. PAD3, but not PAD2, transcripts and citrullination are upregulated and apoptosis is significantly reduced by PAD3, but not PAD2, inhibition. Conversely, PAD inhibition in untreated hNSCs increases proliferation. Furthermore, I found PAD modulates the AIF-mediated apoptosis pathway as PAD is required for AIF cleavage and its translocation to the nucleus. Cytoskeletal association with AIF (previously shown to be disrupted by calcium-induced apoptosis) was also prevented through PAD inhibition. Finally, studies of a novel PAD inhibitor showed that it is more potent than Cl-amidine. Together these findings indicate that PADs mediate neural cell survival/death and identify PAD3 as a new key upstream regulator of calcium-induced apoptosis in human neural cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available