First author: Ferretti, Patrizia (poster)
Poster board A7 - Sun 04/07/2010, 14:30 - Hall 1
Session 040 - Transplantation & regeneration
Abstract n° 040.7
Publication ref.: FENS Abstr., vol.5, 040.7, 2010
||Ferretti P. (1), Lange S. (1), Goegel S. (1), Leung K. T. (2), Nicholas A. P. (3), Thompson P. R. (4) & Greene N. D. E. (2)
||(1) UCL Institute of Child Health, Dev Biol Unit, London, UK; (2) UCL Institute of Child Health, Neural Dev Unit, London, UK; (3) Univ Alabama, Dept Neurology, Birmingham, USA; (4) Univ South Carolina, Dept Chem & Biochem, Columbia, USA
||Spinal cord regeneration: peptidylarginine deiminase (PAD) and epigentic regulation of injury response
||The chick embryo can repair spinal cord damage until around embryonic day (E) 13, but at later stages, spinal cord injury results in structural and functional damage, as in mammals. When effective spinal cord regeneration occurs (E11), secondary injury is much less extensive than at stages non-permissive for regeneration (E15), with limited apoptotic response and no cavity formation. Intracellular calcium increase following neural damage is known to play a key role in secondary injury response. At non-regenerating stages, treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation. We therefore screened for gene expression changes to identify potential mediators of calcium-dependent processes in the injury response.
We found that a peptidylarginine deiminase (PAD) isozyme, PAD3, that converts protein arginine residues to citrulline (citrullination), is among calcium-dependent molecules differentially regulated in response to spinal cord injury at E11 and E15. Citrullination causes a change in net charge and protein conformation that can influence molecular interactions. Consistent with differences in up-regulation of PAD3 in spinal cords injured at E11 and E15, more extensive citrullination was observed at the latter, non-regenerating stage, following injury. Treatment with a specific PAD inhibitor, Cl-amidine, at the time of injury greatly reduced citrullination and secondary injury response in E15 spinal cords, as indicated by decreased apoptosis and cavity size. In order to identify downstream targets of PADs that may account for this reduction in secondary injury response, we analysed proteins immunoprecipitated with an antibody to protein-bound citrulline by mass-spectrometry. A number of putative PAD targets, including histones, were found to be differently expressed in regenerating and non-regenerating spinal cords and their analysis is in progress. Altogether, these findings identify PADs and citrullination as modulators of secondary injury response, suggest that they may play a role in this response via epigenetic mechanisms, and points at PADs as potential therapeutic targets for spinal injury.
||A - Development
Transplantation and regeneration / Spinal cord injury and regeneration
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