Pathogenic upregulation of glial lipocalin-2 in the parkinsonian dopaminergic system

Byung Wook Kim, Kyoung Hoon Jeong, Jae Hong Kim, Myungwon Jin, Jong Heon Kim, Maan Gee Lee, Dong Kug Choi, So Yoon Won, Catriona McLean, Min Tae Jeon, Ho Won Lee, Sang Ryong Kim, Kyoungho Suk

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85 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5608-5622
Number of pages15
JournalThe Journal of Neuroscience
Volume36
Issue number20
DOIs
Publication statusPublished - 18 May 2016
Externally publishedYes

Keywords

  • Astrocyte
  • Lipocalin-2
  • Neurodegeneration
  • Neuroinflammation
  • Parkinson’s disease

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