The post-translational citrullination (deimination) process is mediated by 
peptidylarginine deiminases (PADs), which convert peptidylarginine into 
peptidylcitrulline in the presence of high calcium concentrations. Over the past 
decade, PADs and protein citrullination have been commonly implicated as 
abnormal pathological features in neurodegeneration and inflammatory responses 
associated with diseases such as multiple sclerosis, Alzheimer disease and 
rheumatoid arthritis. Based on this evidence, we investigated the roles of PADs 
and citrullination in the pathogenesis of prion diseases. Prion diseases (also 
known as transmissible spongiform encephalopathies) are fatal neurodegenerative 
diseases that are pathologically well characterized as the accumulation of 
disease-associated misfolded prion proteins, spongiform changes, glial cell 
activation and neuronal loss. We previously demonstrated that the upregulation 
of PAD2, mainly found in reactive astrocytes of infected brains, leads to 
excessive citrullination, which is correlated with disease progression. Further, 
we demonstrated that various cytoskeletal and energy metabolism-associated 
proteins are particularly vulnerable to citrullination. Our recent in vivo and 
in vitro studies elicited altered functions of enolase as the result of 
citrullination; these altered functions included reduced enzyme activity, 
increased protease sensitivity and enhanced plasminogen-binding affinity. These 
findings suggest that PAD2 and citrullinated proteins may play a key role in the 
brain pathology of prion diseases. By extension, we believe that abnormal 
increases in protein citrullination may be strong evidence of neurodegeneration.