• the Korean Society for Brain and Neural Sciences


Review Article

Exp Neurobiol 2016; 25(4): 147-155

Published online August 31, 2016

© The Korean Society for Brain and Neural Sciences

Prothrombin Kringle-2: A Potential Inflammatory Pathogen in the Parkinsonian Dopaminergic System

Eunju Leem1,2#, Kyoung Hoon Jeong1,2#, So-Yoon Won4, Won-Ho Shin5* and Sang Ryong Kim1,2,3,6*

1School of Life Sciences & Biotechnology, 2BK21 plus KNU Creative BioResearch Group, 3Institute of Life Science & Biotechnology, Kyungpook National University, Daegu 41566, 4Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, 5Predictive Research Center, Korea Institute of Toxicology, Daejeon 34114, 6Brain Science and Engineering Institute, Kyungpook National University, Daegu 41944, Korea

Correspondence to: *To whom correspondence should be addressed.
Sang Ryong Kim, TEL: 82-53-950-7362, FAX: 82-53-943-2762
Won-Ho Shin, TEL: 82-42-610-8088, FAX: 82-42-610-8157
#These authors contributed equally to this work.

Received: July 13, 2016; Revised: July 29, 2016; Accepted: July 30, 2016


Although accumulating evidence suggests that microglia-mediated neuroinflammation may be crucial for the initiation and progression of Parkinson's disease (PD), and that the control of neuroinflammation may be a useful strategy for preventing the degeneration of nigrostriatal dopaminergic (DA) projections in the adult brain, it is still unclear what kinds of endogenous biomolecules initiate microglial activation, consequently resulting in neurodegeneration. Recently, we reported that the increase in the levels of prothrombin kringle-2 (pKr-2), which is a domain of prothrombin that is generated by active thrombin, can lead to disruption of the nigrostriatal DA projection. This disruption is mediated by neurotoxic inflammatory events via the induction of microglial Toll-like receptor 4 (TLR4) in vivo , thereby resulting in less neurotoxicity in TLR4-deficient mice. Moreover, inhibition of microglial activation following minocycline treatment, which has anti-inflammatory activity, protects DA neurons from pKr-2-induced neurotoxicity in the substantia nigra (SN) in vivo. We also found that the levels of pKr-2 and microglial TLR4 were significantly increased in the SN of PD patients compared to those of age-matched controls. These observations suggest that there may be a correlation between pKr-2 and microglial TLR4 in the initiation and progression of PD, and that inhibition of pKr-2-induced microglial activation may be protective against the degeneration of the nigrostriatal DA system in vivo. To describe the significance of pKr-2 overexpression, which may have a role in the pathogenesis of PD, we have reviewed the mechanisms of pKr-2-induced microglial activation, which results in neurodegeneration in the SN of the adult brain.

Keywords: Prothrombin kringle-2, Parkinson’s disease, Microglia, Toll-like receptor 4