Journal of Stem Cell Research & Therapy

Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminaseâ?? AIF pathway

4^th International Conference and Exhibition on Cell & Gene Therapy

August 10-12, 2015 London, UK

Kin Pong U1, Venkataraman Subramanian2, Antony P Nicholas3, Paul R Thompson2 and Patrizia Ferretti1

Posters-Accepted Abstracts: J Stem Cell Res Ther

Abstract:

PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline
(citrullination/ deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord
injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem
cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target
for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a
modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for
AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage
required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly
and association of PAD3 with vimentin that we show to be associated also with AIF; together this suggests that PAD-dependent
cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of
PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced
apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved.