title: Induction of microglial toll-like receptor 4 by prothrombin kringle-2: a potential pathogenic mechanism in Parkinson's disease.
abstract: Microglia-mediated neuroinflammation may play an important role in the initiation and progression of dopaminergic (DA) neurodegeneration in Parkinson's disease (PD), and toll-like receptor 4 (TLR4) is essential for the activation of microglia in the adult brain. However, it is still unclear whether patients with PD exhibit an increase in TLR4 expression in the brain, and whether there is a correlation between the levels of prothrombin kringle-2 (pKr-2) and microglial TLR4. In the present study, we first observed that the levels of pKr-2 and microglial TLR4 were increased in the substantia nigra (SN) of patients with PD. In rat and mouse brains, intranigral injection of pKr-2, which is not directly toxic to neurons, led to the disruption of nigrostriatal DA projections. Moreover, microglial TLR4 was upregulated in the rat SN and in cultures of the BV-2 microglial cell line after pKr-2 treatment. In TLR4-deficient mice, pKr-2-induced microglial activation was suppressed compared with wild-type mice, resulting in attenuated neurotoxicity. Therefore, our results suggest that pKr-2 may be a pathogenic factor in PD, and that the inhibition of pKr-2-induced microglial TLR4 may be protective against degeneration of the nigrostriatal DA system in vivo.
authors.affiliation: School of Life Sciences, Kyungpook National University, Daegu 702-701, Korea.|College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea.|Next-generation pharmaceutical research center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon, 305-343, Korea.
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Shin
authors.affiliation: School of Life Sciences, Kyungpook National University, Daegu 702-701, Korea.|BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Min-Tae
authors.initials: MT
authors.lastname: Jeon
authors.affiliation: School of Life Sciences, Kyungpook National University, Daegu 702-701, Korea.|BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Eunju
authors.initials: E
authors.lastname: Leem
authors.affiliation: Department of Biochemistry and Medical Research Center, Chungbuk National University College of Medicine, Cheongju 361-763, Korea.
authors.forename: So-Yoon
authors.initials: SY
authors.lastname: Won
authors.affiliation: School of Life Sciences, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Kyoung Hoon
authors.initials: KH
authors.lastname: Jeong
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Victorian Brain Bank Network, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC 3004, Australia.|Department of Anatomical Pathology, Alfred Hospital, Melbourne, VIC 3004, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.affiliation: Department of Neuroscience and Physiology, School of Dentistry, Seoul National University, Seoul, 110-749, Korea.|Dental Research Institute, School of Dentistry, Seoul National University, Seoul, 110-749, Korea.
authors.forename: Sung Joong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry &Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.|Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Byung Kwan
authors.initials: BK
authors.lastname: Jin
authors.affiliation: School of Life Sciences, Kyungpook National University, Daegu 702-701, Korea.|Department of Food Science and Nutrition, Pukyong National University, Busan 608-737, Korea.
authors.forename: Un Ju
authors.initials: UJ
authors.lastname: Jung
authors.affiliation: School of Life Sciences, Kyungpook National University, Daegu 702-701, Korea.|BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Korea.|Institute of Life Science &Biotechnology, Kyungpook National University, Daegu 702-701, Korea.|Brain Science and Engineering Institute, Kyungpook National University, Daegu 700-842, Korea.
authors.forename: Sang Ryoung
authors.initials: SR
authors.lastname: Kim
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D018082:Kringles; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011516:Prothrombin / Q000378:metabolism* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011516:Prothrombin; D004298:Dopamine