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JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss
BACKGROUND: Amplified inflammation is important for the progression of Parkinson’s disease (PD). However, how this enhanced inflammation is regulated remains largely unknown. Deletion of DICER leads to progressive dopamine neuronal loss and induces gliosis. We hypothesized that the homeostasis of mi...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003208/ https://www.ncbi.nlm.nih.gov/pubmed/29907159 http://dx.doi.org/10.1186/s12974-018-1218-1 |
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author | Wang, Qing He, Qian Chen, Yifei Shao, Wei Yuan, Chao Wang, Yizheng |
author_facet | Wang, Qing He, Qian Chen, Yifei Shao, Wei Yuan, Chao Wang, Yizheng |
author_sort | Wang, Qing |
collection | PubMed |
description | BACKGROUND: Amplified inflammation is important for the progression of Parkinson’s disease (PD). However, how this enhanced inflammation is regulated remains largely unknown. Deletion of DICER leads to progressive dopamine neuronal loss and induces gliosis. We hypothesized that the homeostasis of microglial DICER would be responsible for the amplified inflammation in the mouse model of PD. METHODS: The microglia or C57BL/6 mice were treated or injected with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)), respectively, for the model establishment. Microglia and astrocytes sorted by fluorescence-activated cell sorter (FACS) were assayed by quantitative real-time PCR, Western blotting, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), immunohistofluorescence, and mass spectrometry. RESULTS: Microglial DICER was phosphorylated at serine 1456 by c-jun N-terminal kinase (JNK) and downregulated in response to 1-methyl-4-phenylpyridinium (MPP(+)), a causative agent in PD. Inhibition of JNK phosphorylation of DICER at serine 1456 rescued the MPP(+)-induced DICER degradation, suppressed microglial inflammatory process, and prevented the loss of tyrosine hydroxylase-expressing neurons in the mouse MPTP model. CONCLUSIONS: JNK-mediated microglial DICER degradation potentiates inflammation to induce dopaminergic neuronal loss. Thus, preventing microglial DICER degradation could be a novel strategy for controlling neuroinflammation in PD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1218-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6003208 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-60032082018-06-26 JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss Wang, Qing He, Qian Chen, Yifei Shao, Wei Yuan, Chao Wang, Yizheng J Neuroinflammation Research BACKGROUND: Amplified inflammation is important for the progression of Parkinson’s disease (PD). However, how this enhanced inflammation is regulated remains largely unknown. Deletion of DICER leads to progressive dopamine neuronal loss and induces gliosis. We hypothesized that the homeostasis of microglial DICER would be responsible for the amplified inflammation in the mouse model of PD. METHODS: The microglia or C57BL/6 mice were treated or injected with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)), respectively, for the model establishment. Microglia and astrocytes sorted by fluorescence-activated cell sorter (FACS) were assayed by quantitative real-time PCR, Western blotting, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), immunohistofluorescence, and mass spectrometry. RESULTS: Microglial DICER was phosphorylated at serine 1456 by c-jun N-terminal kinase (JNK) and downregulated in response to 1-methyl-4-phenylpyridinium (MPP(+)), a causative agent in PD. Inhibition of JNK phosphorylation of DICER at serine 1456 rescued the MPP(+)-induced DICER degradation, suppressed microglial inflammatory process, and prevented the loss of tyrosine hydroxylase-expressing neurons in the mouse MPTP model. CONCLUSIONS: JNK-mediated microglial DICER degradation potentiates inflammation to induce dopaminergic neuronal loss. Thus, preventing microglial DICER degradation could be a novel strategy for controlling neuroinflammation in PD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1218-1) contains supplementary material, which is available to authorized users. BioMed Central 2018-06-15 /pmc/articles/PMC6003208/ /pubmed/29907159 http://dx.doi.org/10.1186/s12974-018-1218-1 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Wang, Qing He, Qian Chen, Yifei Shao, Wei Yuan, Chao Wang, Yizheng JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss |
title | JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss |
title_full | JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss |
title_fullStr | JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss |
title_full_unstemmed | JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss |
title_short | JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss |
title_sort | jnk-mediated microglial dicer degradation potentiates inflammatory responses to induce dopaminergic neuron loss |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003208/ https://www.ncbi.nlm.nih.gov/pubmed/29907159 http://dx.doi.org/10.1186/s12974-018-1218-1 |
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