Published online before print September 11, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2008.080388v1 173/4/1129    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jang, B. Articles by Choi, E.-K. Search for Related Content PubMed PubMed Citation Articles by Jang, B. Articles by Choi, E.-K.

(American Journal of Pathology. 2008;173:1129-1142.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080388

Accumulation of Citrullinated Proteins by Up-Regulated Peptidylarginine Deiminase 2 in Brains of Scrapie-Infected Mice

A Possible Role in Pathogenesis

Byungki Jang^*, Eunah Kim^*, Jin-Kyu Choi^*, Jae-Kwang Jin^*, Jae-Il Kim, Akihito Ishigami, Naoki Maruyama, Richard I. Carp, Yong-Sun Kim^* and Eun-Kyoung Choi^*

From the Ilsong Institute of Life Science,^* Hallym University, Anyang, Republic of Korea; the Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea; the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York; and the Aging Regulation, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

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.