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Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice

Astrocytic JWA exerts neuroprotective roles by alleviating oxidative stress and inhibiting inflammation. However, the molecular mechanisms of how astrocytic JWA is involved in dopaminergic neurodegeneration in Parkinson’s disease (PD) remain largely unknown. In this study, we found that astrocyte-sp...

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Autores principales: Wang, Rihua, Zhao, Xue, Xu, Jin, Wen, Yifan, Li, Aiping, Lu, Ming, Zhou, Jianwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834463/
https://www.ncbi.nlm.nih.gov/pubmed/29500411
http://dx.doi.org/10.1038/s41419-018-0381-8
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author Wang, Rihua
Zhao, Xue
Xu, Jin
Wen, Yifan
Li, Aiping
Lu, Ming
Zhou, Jianwei
author_facet Wang, Rihua
Zhao, Xue
Xu, Jin
Wen, Yifan
Li, Aiping
Lu, Ming
Zhou, Jianwei
author_sort Wang, Rihua
collection PubMed
description Astrocytic JWA exerts neuroprotective roles by alleviating oxidative stress and inhibiting inflammation. However, the molecular mechanisms of how astrocytic JWA is involved in dopaminergic neurodegeneration in Parkinson’s disease (PD) remain largely unknown. In this study, we found that astrocyte-specific JWA knockout mice (JWA CKO) exacerbated dopamine (DA) neuronal loss and motor dysfunction, and reduced the levels of DA and its metabolites in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model. Astrocytic JWA deficiency repressed expression of excitatory amino-acid transporter 2 (GLT-1) and glutamate uptake both in vivo and in vitro. Further, the regulation of GLT-1 expression was involved in JWA-triggered activation of the MAPK and PI3K signaling pathways. JWA-increased GLT-1 expression was abolished by inhibitors of MEK and PI3K. Silencing CREB also abrogated JWA-increased GLT-1 expression and glutamate uptake. Additionally, JWA deficiency activated glial fibrillary acidic protein (GFAP), and increased the expression of STAT3. Similarly to the MPTP model, paraquat (PQ) exposure produced PD-like phenotypes in JWA CKO mice. Taken together, our findings provide novel insights into astrocytic JWA function in the pathogenesis of neurotoxin mouse models of PD.
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spelling pubmed-58344632018-03-06 Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice Wang, Rihua Zhao, Xue Xu, Jin Wen, Yifan Li, Aiping Lu, Ming Zhou, Jianwei Cell Death Dis Article Astrocytic JWA exerts neuroprotective roles by alleviating oxidative stress and inhibiting inflammation. However, the molecular mechanisms of how astrocytic JWA is involved in dopaminergic neurodegeneration in Parkinson’s disease (PD) remain largely unknown. In this study, we found that astrocyte-specific JWA knockout mice (JWA CKO) exacerbated dopamine (DA) neuronal loss and motor dysfunction, and reduced the levels of DA and its metabolites in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model. Astrocytic JWA deficiency repressed expression of excitatory amino-acid transporter 2 (GLT-1) and glutamate uptake both in vivo and in vitro. Further, the regulation of GLT-1 expression was involved in JWA-triggered activation of the MAPK and PI3K signaling pathways. JWA-increased GLT-1 expression was abolished by inhibitors of MEK and PI3K. Silencing CREB also abrogated JWA-increased GLT-1 expression and glutamate uptake. Additionally, JWA deficiency activated glial fibrillary acidic protein (GFAP), and increased the expression of STAT3. Similarly to the MPTP model, paraquat (PQ) exposure produced PD-like phenotypes in JWA CKO mice. Taken together, our findings provide novel insights into astrocytic JWA function in the pathogenesis of neurotoxin mouse models of PD. Nature Publishing Group UK 2018-03-02 /pmc/articles/PMC5834463/ /pubmed/29500411 http://dx.doi.org/10.1038/s41419-018-0381-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Rihua
Zhao, Xue
Xu, Jin
Wen, Yifan
Li, Aiping
Lu, Ming
Zhou, Jianwei
Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
title Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
title_full Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
title_fullStr Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
title_full_unstemmed Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
title_short Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
title_sort astrocytic jwa deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834463/
https://www.ncbi.nlm.nih.gov/pubmed/29500411
http://dx.doi.org/10.1038/s41419-018-0381-8
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