Peptidylarginine deiminases (PADs), which are a group of posttranslational 
modification enzymes, are involved in protein citrullination (deimination) by 
the conversion of peptidylarginine to peptidylcitrulline in a calcium 
concentration-dependent manner. Among the PADs, PAD2 is widely distributed in 
various tissues and is the only type that is expressed in brain. To elucidate 
the involvement of protein citrullination by PAD2 in the pathogenesis of 
brain-specific prion diseases, we examined the profiles of citrullinated 
proteins using the brains of scrapie-infected mice as a prion disease model. We 
found that, compared with controls, increased levels of citrullinated proteins 
of various molecular weights were detected in different brain sections of 
scrapie-infected mice. In support of this data, expression levels of PAD2 
protein as well as its enzyme activity were significantly increased in brain 
sections of scrapie-infected mice, including hippocampus, brain stem, and 
striatum. Additionally, the expression levels of PAD2 mRNA were increased during 
scrapie infection. Moreover, PAD2 immunoreactivity was increased in 
scrapie-infected brains, with staining detected primarily in reactive 
astrocytes. Using two-dimensional electrophoresis and matrix-assisted laser 
desorption/ionization-time of flight mass spectrometry, various citrullinated 
proteins were identified in the brains of scrapie-infected mice, including glial 
fibrillary acidic protein, myelin basic protein, enolases, and aldolases. This 
study suggests that accumulated citrullinated proteins and abnormal activation 
of PAD2 may function in the pathogenesis of prion diseases and serve as 
potential therapeutic targets.