Accumulation of citrullinated proteins by up-regulated peptidylarginine deiminase 2 in brains of scrapie-infected mice: a possible role in pathogenesis.
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.
Jang
Byungki
B
Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.
Kim
Eunah
E
Choi
Jin-Kyu
JK
Jin
Jae-Kwang
JK
Kim
Jae-Il
JI
Ishigami
Akihito
A
Maruyama
Naoki
N
Carp
Richard I
RI
Kim
Yong-Sun
YS
Choi
Eun-Kyoung
EK
D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D002956:Citrulline / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D005455:Fluorescent Antibody Technique; D005634:Fructose-Bisphosphate Aldolase / Q000737:chemistry / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000737:chemistry / Q000378:metabolism; D006867:Hydrolases / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000737:chemistry / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000737:chemistry / Q000378:metabolism; D018620:PrPSc Proteins / Q000472:pathogenicity*; D021381:Protein Transport; D000076342:Protein-Arginine Deiminases; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015854:Up-Regulation / Q000235:genetics*
D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D018620:PrPSc Proteins; D011506:Proteins; D002956:Citrulline; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases; D005634:Fructose-Bisphosphate Aldolase; D010751:Phosphopyruvate Hydratase
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