Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice.
Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice.
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星形胶质细胞 JWA 缺失通过减少小鼠谷氨酸转运蛋白加剧多巴胺能神经变性
DOI：
10.1038/s41419-018-0381-8
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发表时间：
2018-03-02
影响因子：
9
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Wang R;Zhao X;Xu J;Wen Y;Li A;Lu M;Zhou J
星形胶质细胞JWA通过减轻氧化应激和抑制炎症发挥神经保护作用。然而，星形胶质细胞JWA如何参与帕金森病（PD）多巴胺能神经变性的分子机制仍不清楚。在本研究中，我们发现星形胶质细胞特异性JWA基因敲除小鼠（JWA CKO）加重了多巴胺（DA）神经元丢失和运动功能障碍，并降低了1-甲基-4-苯基-1，2，3，6-四氢吡啶/丙磺舒（MPTP/p）诱导的PD模型中DA及其代谢产物的水平。星形胶质细胞JWA缺陷抑制兴奋性氨基酸转运蛋白2（GLT-1）的表达和谷氨酸摄取在体内和体外。此外，GLT-1表达的调节涉及JWA触发的MAPK和PI 3 K信号通路的激活。JWA增加的GLT-1表达被MEK和PI 3 K抑制剂消除。沉默CREB也消除了JWA增加的GLT-1表达和谷氨酸摄取。此外，JWA缺乏激活胶质细胞酸性蛋白（GFAP），并增加STAT 3的表达。与MPTP模型类似，百草枯（PQ）暴露在JWA CKO小鼠中产生了PD样表型。总之，我们的研究结果提供了新的见解星形胶质细胞JWA功能的发病机制的神经毒素小鼠模型的PD。
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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影响因子：
34.7
作者：
Clarke, Laura E.;Barres, Ben A.
通讯作者：
Barres, Ben A.
影响因子：
64.8
作者：
Lin, CLG;Orlov, I;Rothstein, JD
通讯作者：
Rothstein, JD
影响因子：
6.2
作者：
Ji, Yi-Fei;Zhou, Liang;Shen, Ying
通讯作者：
Shen, Ying
星形胶质细胞疤痕形成有助于中枢神经系统轴突再生。
影响因子：
64.8
作者：
Anderson MA;Burda JE;Ren Y;Ao Y;O'Shea TM;Kawaguchi R;Coppola G;Khakh BS;Deming TJ;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
2.9
作者：
Farrand AQ;Gregory RA;Bäckman CM;Helke KL;Boger HA
通讯作者：
Boger HA