Protein deiminases: new players in the developmentally regulated loss of neural regenerative ability.
Nicholas, Anthony P.
Causey, Corey P.
Thompson, Paul R
Greene, Nicholas D.E.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
Gene Expression Regulation, Developmental
In Situ Nick-End Labeling
Oligonucleotide Array Sequence Analysis
Spinal Cord Injuries
Spinal Cord Regeneration
Enzymes and Coenzymes
MetadataShow full item record
AbstractSpinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective regeneration does not occur after E13, when spinal cord injury induces extensive apoptotic response and tissue damage. As initial experiments showed that treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation, we hypothesized that developmentally regulated mediators of calcium-dependent processes in secondary injury response may contribute to loss of regenerative ability. To this purpose we screened for such changes in chick spinal cords at stages of development permissive (E11) and non-permissive (E15) for regeneration. Among the developmentally regulated calcium-dependent proteins identified was PAD3, a member of the peptidylarginine deiminase (PAD) enzyme family that converts protein arginine residues to citrulline, a process known as deimination or citrullination. This post-translational modification has not been previously associated with response to injury. Following injury, PAD3 up-regulation was greater in spinal cords injured at E15 than at E11. Consistent with these differences in gene expression, deimination was more extensive at the non-regenerating stage, E15, both in the gray and white matter. As deimination paralleled the extent of apoptosis, we investigated the effect of blocking PAD activity on cell death and deiminated-histone 3, one of the PAD targets we identified by mass-spectrometry analysis of spinal cord deiminated proteins. Treatment with the PAD inhibitor, Cl-amidine, reduced the abundance of deiminated-histone 3, consistent with inhibition of PAD activity, and significantly reduced apoptosis and tissue loss following injury at E15. Altogether, our findings identify PADs and deimination as developmentally regulated modulators of secondary injury response, and suggest that PADs might be valuable therapeutic targets for spinal cord injury.
SourceDev Biol. 2011 Jul 15;355(2):205-14. doi: 10.1016/j.ydbio.2011.04.015. Epub 2011 Apr 22. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/50037
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related ResourcesLink to Article in PubMed