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Involvement of peptidylarginine deiminase-mediated post-translational citrullination in pathogenesis of sporadic Creutzfeldt-Jakob disease

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Abstract

Peptidylarginine deiminases (PADs)-mediated post-translational citrullination processes play key roles in protein functions and structural stability through the conversion of arginine to citrulline in the presence of excessive calcium concentrations. In brain, PAD2 is abundantly expressed and can be involved in citrullination in disease. Recently, we have reported pathological characterization of PAD2 and citrullinated proteins in scrapie-infected mice, but the implication of protein citrullination in the pathophysiology in human prion disease is not clear. In the present study, we explored the molecular and biological involvement of PAD2 and the pathogenesis of citrullinated proteins in frontal cortex of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We found increased expression of PAD2 in reactive astrocytes that also contained increased levels of citrullinated proteins. In addition, PAD activity was significantly elevated in patients with sCJD compared to controls. From two-dimensional gel electrophoresis and MALDI-TOF mass analysis, we found various citrullinated candidates, including cytoskeletal and energy metabolism-associated proteins such as vimentin, glial fibrillary acidic protein, enolase, and phosphoglycerate kinase. Based on these findings, our investigations suggest that PAD2 activation and aberrant citrullinated proteins could play a role in pathogenesis and have value as a marker for the postmortem classification of neurodegenerative diseases.

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Abbreviations

PAD:

Peptidylarginine deiminase

CJD:

Creutzfeldt-Jakob disease

PrP:

Prion protein

CNS:

Central nervous system

2-DE:

Two-dimensional gel electrophoresis

MALDI-TOF mass:

Matrix-assisted laser desorption/ionization-time of flight mass

BAEE:

Benzoyl-l-arginine ethyl ester

SDS:

Sodium dodecyl sulfate

anti-MC:

Anti-modified citrulline

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

MBP:

Myelin basic protein

AD:

Alzheimer’s disease

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Acknowledgments

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A085082).

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Authors and Affiliations

  1. Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea

    Byungki Jang, Jae-Kwang Jin, Yong-Chul Jeon, Han Jeong Cho, Yong-Sun Kim & Eun-Kyoung Choi

  2. Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea

    Byungki Jang & Yong-Sun Kim

  3. Department of Pathology, College of Medicine, Hallym University, Chuncheon, Republic of Korea

    Kyung-Chan Choi

  4. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan

    Akihito Ishigami

  5. Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan

    Akihito Ishigami & Naoki Maruyama

  6. New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA

    Richard I. Carp

  7. Laboratory of Cellular Aging and Neurodegeneration, Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi-do, 431-060, Republic of Korea

    Eun-Kyoung Choi

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  1. Byungki Jang
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Jang, B., Jin, JK., Jeon, YC. et al. Involvement of peptidylarginine deiminase-mediated post-translational citrullination in pathogenesis of sporadic Creutzfeldt-Jakob disease. Acta Neuropathol 119, 199–210 (2010). https://doi.org/10.1007/s00401-009-0625-x

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  • DOI: https://doi.org/10.1007/s00401-009-0625-x

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