title: Peptidylarginine deiminase and protein citrullination in prion diseases: strong evidence of neurodegeneration.
abstract: 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.
authors.affiliation: Laboratory of Cellular Aging and Neurodegeneration, Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.
authors.forename: Byungki
authors.initials: B
authors.lastname: Jang
authors.forename: Akihito
authors.initials: A
authors.lastname: Ishigami
authors.forename: Naoki
authors.initials: N
authors.lastname: Maruyama
authors.forename: Richard I
authors.initials: RI
authors.lastname: Carp
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002956:Citrulline / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D017096:Prion Diseases / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D011328:Prions / Q000378:metabolism; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D011506:Proteins / Q000378:metabolism
chemical_list: D011328:Prions; D011506:Proteins; D002956:Citrulline; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases