title: Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System.
abstract: Lipocalin-2 (LCN2) is a member of the highly heterogeneous secretory protein family of lipocalins and increases in its levels can contribute to neurodegeneration in the adult brain. However, there are no reports on the role of LCN2 in Parkinson's disease (PD). Here, we report for the first time that LCN2 expression is increased in the substantia nigra (SN) of patients with PD. In mouse brains, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment for a neurotoxin model of PD significantly upregulated LCN2 expression, mainly in reactive astrocytes in both the SN and striatum. The increased LCN2 levels contributed to neurotoxicity and neuroinflammation, resulting in disruption of the nigrostriatal dopaminergic (DA) projection and abnormal locomotor behaviors, which were ameliorated in LCN2-deficient mice. Similar to the effects of MPTP treatment, LCN2-induced neurotoxicity was also observed in the 6-hydroxydopamine (6-OHDA)-treated animal model of PD. Moreover, treatment with the iron donor ferric citrate (FC) and the iron chelator deferoxamine mesylate (DFO) increased and decreased, respectively, the LCN2-induced neurotoxicity in vivo In addition to the in vivo results, 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in cocultures of mesencephalic neurons and astrocytes was reduced by LCN2 gene deficiency in the astrocytes and conditioned media derived from MPP(+)-treated SH-SY5Y neuronal enhanced glial expression of LCN2 in vitro Therefore, our results demonstrate that astrocytic LCN2 upregulation in the lesioned DA system may play a role as a potential pathogenic factor in PD and suggest that inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal DA system in the adult brain.
  
  
  
  Lipocalin-2 (LCN2), a member of the highly heterogeneous secretory protein family of lipocalins, may contribute to neuroinflammation and neurotoxicity in the brain. However, LCN2 expression and its role in Parkinson's disease (PD) are largely unknown. Here, we report that LCN2 is upregulated in the substantia nigra of patients with PD and neurotoxin-treated animal models of PD. Our results suggest that LCN2 upregulation might be a potential pathogenic mechanism of PD, which would result in disruption of the nigrostriatal dopaminergic system through neurotoxic iron accumulation and neuroinflammation. Therefore, inhibition of LCN2 expression or activity may be useful in protecting the nigrostriatal dopaminergic projection in PD.
authors.affiliation: Department of Pharmacology, BK21 plus KNU Biomedical Convergence Program, Brain Science and Engineering Institute, and Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju 27478, Korea.
authors.forename: Byung-Wook
authors.identifier: 0000-0001-8390-7713
authors.initials: BW
authors.lastname: Kim
authors.affiliation: School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea.
authors.forename: Kyoung Hoon
authors.identifier: 0000-0002-6100-9936
authors.initials: KH
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology, BK21 plus KNU Biomedical Convergence Program, Brain Science and Engineering Institute, and.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, BK21 plus KNU Biomedical Convergence Program, Brain Science and Engineering Institute, and.
authors.forename: Myungwon
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, BK21 plus KNU Biomedical Convergence Program, Brain Science and Engineering Institute, and.
authors.forename: Jong-Heon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, BK21 plus KNU Biomedical Convergence Program, Brain Science and Engineering Institute, and.
authors.forename: Maan-Gee
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju 27478, Korea.
authors.forename: Dong-Kug
authors.initials: DK
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Medical Research Center, Chungbuk National University College of Medicine, Cheongju 28644, Korea.
authors.forename: So-Yoon
authors.initials: SY
authors.lastname: Won
authors.affiliation: Victorian Brain Bank Network, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC 3004, Australia, and Department of Anatomical Pathology, Alfred Hospital, Melbourne, VIC 3004, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.affiliation: School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea.
authors.forename: Min-Tae
authors.initials: MT
authors.lastname: Jeon
authors.affiliation: Brain Science and Engineering Institute, and Department of Neurology, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
authors.forename: Ho-Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Brain Science and Engineering Institute, and School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea, ksuk@knu.ac.kr srk75@knu.ac.kr.
authors.forename: Sang Ryong
authors.identifier: 0000-0003-0299-1613
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, BK21 plus KNU Biomedical Convergence Program, Brain Science and Engineering Institute, and ksuk@knu.ac.kr srk75@knu.ac.kr.
authors.forename: Kyoungho
authors.identifier: 0000-0002-9555-4203
authors.initials: K
authors.lastname: Suk
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D059290:Dopaminergic Neurons / Q000378:metabolism; D005260:Female; D006801:Humans; D000071068:Lipocalin-2 / Q000235:genetics / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000071068:Lipocalin-2
keywords: Parkinson's disease; astrocyte; lipocalin-2; neurodegeneration; neuroinflammation