Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System
| Autor: | Catriona McLean, So-Yoon Won, Jong-Heon Kim, Ho-Won Lee, Byung-Wook Kim, Kyoung Hoon Jeong, Maan-Gee Lee, Jae-Hong Kim, Min-Tae Jeon, Dong-Kug Choi, Myungwon Jin, Sang Ryong Kim, Kyoungho Suk |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Substantia nigra Pharmacology Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Lipocalin-2 medicine Animals Humans Neurotoxin Neuroinflammation Aged Aged 80 and over Deferoxamine mesylate Dopaminergic Neurons General Neuroscience MPTP Dopaminergic Neurotoxicity MPTP Poisoning Parkinson Disease Articles medicine.disease Up-Regulation Mice Inbred C57BL Substantia Nigra 030104 developmental biology chemistry Case-Control Studies Female Neuroglia Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Neuroscience. 36:5608-5622 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.4261-15.2016 |
| Popis: | 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 neurotoxicityin vivo. In addition to thein vivoresults, 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 LCN2in 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.SIGNIFICANCE STATEMENTLipocalin-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. |
| Databáze: | OpenAIRE |
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