Peptidylarginine deiminases (PADs) are a group of posttranslational modification 
enzymes that citrullinate (deiminate) protein arginine residues in a 
Ca(2+)-dependent manner. Enzymatic citrullination abolishes positive charges of 
native protein molecules, inevitably causing significant alterations in their 
structure and functions. Among the five isoforms of PADs, PAD2 and PAD4 are 
proved occupants of the central nervous system (CNS), and especially PAD2 is a 
main PAD enzyme expressed in the CNS. We previously reported that abnormal 
protein citrullination by PAD2 has been closely associated with the pathogenesis 
of neurodegenerative disorders such as Alzheimer's disease and prion disease. 
Protein citrullination in these patients is thought to play a role during the 
initiation and/or progression of disease. However, the contribution of changes 
in PAD2 levels, and consequent citrullination, during developmental and aging 
processes remained unclear. Therefore, we used quantitative real-time RT-PCR, 
Western blot analysis, and immunohistochemical methods to measure PAD2 
expression and localization in the brain during those processes. PAD2 mRNA 
expression was detected in the brains of mice as early as embryonic day 15, and 
its expression in cerebral cortex, hippocampus, and cerebellum increased 
significantly as the animals aged from 3 to 30 months old. No citrullinated 
proteins were detected during that period. Moreover, we found here, for the 
first time, that PAD2 localized specifically in the neuronal cells of the 
cerebral cortex and Purkinje cells of the cerebellum. These findings indicate 
that, despite PAD2's normally inactive status, it becomes active and 
citrullinates cellular proteins, but only when the intracellular Ca(2+) balance 
is upset during neurodegenerative changes.