α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes.
α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes.
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α-突触核蛋白通过干扰星形胶质细胞中的 β-arrestin2-TAB1 相互作用来破坏 Drd2 的抗炎作用
DOI：
10.1186/s12974-018-1302-6
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发表时间：
2018-09-10
影响因子：
9.3
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Du RH;Zhou Y;Xia ML;Lu M;Ding JH;Hu G
α-突触核蛋白(α-Syn)诱导的神经炎症在帕金森病(PD)的发病机制中起着重要作用。多巴胺D2受体(Drd2)被认为是治疗神经退行性疾病的潜在抗炎靶点。然而，星形细胞DRD2在α-Syn诱导的神经炎症中的作用尚不清楚。在体外培养的小鼠原代星形胶质细胞和体内A53T转基因小鼠上观察了Drd2对神经炎症的影响。免疫荧光、酶联免疫吸附试验和定量逆转录聚合酶链式反应检测星形胶质细胞的炎症反应。用Western blotting和蛋白质-蛋白质相互作用分析来评估分子机制的细节。我们发现选择性Drd2激动剂奎比罗抑制野生型小鼠中脑的炎症，但不能抑制α-syn过表达的小鼠的炎症。我们还发现，DRD2激动剂能显著减轻脂多糖诱导的星形胶质细胞炎症反应，但不能抑制α-Syn诱导的炎症反应。DRD2的抗炎作用依赖于β-arrestin2介导的信号转导，而不是经典的G蛋白通路。α-Syn降低星形胶质细胞β-arrestin2的表达。在β-Syn诱导的炎症反应中，DRD2的抗炎作用中恢复了α-arrestin2的表达。此外，我们还发现α-Syn通过抑制β-arrestin2与转化生长因子-β-激活蛋白结合蛋白1(TAB1)的结合和促进Tak1-TAB1在星形胶质细胞中的相互作用来阻断DRD2的抗炎作用。我们的研究表明，星形细胞DRD2通过β抑制蛋白2依赖的机制抑制神经炎症，为帕金森病的治疗提供了新的策略。我们的研究结果还表明，α-Syn在帕金森病的发病机制中干扰了β-arrestin2的功能和炎症通路。
α-Synuclein (α-Syn)-induced neuroinflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Dopamine D2 receptor (Drd2) has been regarded as a potential anti-inflammatory target in the therapy of neurodegenerative diseases. However, the effect of astrocytic Drd2 in α-Syn-induced neuroinflammation remains unclear. The effect of Drd2 on neuroinflammation was examined in mouse primary astrocyte in vitro and A53T transgenic mice in vivo. The inflammatory responses of astrocyte were detected using immunofluorescence, ELISA, and qRT-PCR. The details of molecular mechanism were assessed using Western blotting and protein-protein interaction assays. We showed that the selective Drd2 agonist quinpirole suppressed inflammation in the midbrain of wild-type mice, but not in α-Syn-overexpressed mice. We also found that Drd2 agonists significantly alleviated LPS-induced inflammatory response in astrocytes, but failed to suppress α-Syn-induced inflammatory response. The anti-inflammation effect of Drd2 was dependent on β-arrestin2-mediated signaling, but not classical G protein pathway. α-Syn reduced the expression of β-arrestin2 in astrocytes. Increased the β-arrestin2 expression restored in the anti-inflammation of Drd2 in α-Syn-induced inflammation. Furthermore, we demonstrated that α-Syn disrupted the anti-inflammation of Drd2 via inhibiting the association of β-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and promoting TAK1-TAB1 interaction in astrocytes. Our study illustrates that astrocytic Drd2 inhibits neuroinflammation through a β-arrestin2-dependent mechanism and provides a new strategy for treatment of PD. Our findings also reveal that α-Syn disrupts the function of β-arrestin2 and inflammatory pathways in the pathogenesis of PD.
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影响因子：
12.4
作者：
Feng, X.;Wu, C-Y;Wei, L-N
通讯作者：
Wei, L-N
影响因子：
3.3
作者：
Sadeghi, Heibatollah;Parishani, Mohammad;Sadeghi, Hossein
通讯作者：
Sadeghi, Hossein
影响因子：
64.5
作者：
Saijo K;Collier JG;Li AC;Katzenellenbogen JA;Glass CK
通讯作者：
Glass CK
影响因子：
3.5
作者：
Lastres-Becker, Isabel;Ulusoy, Ayse;Cuadrado, Antonio
通讯作者：
Cuadrado, Antonio
影响因子：
3.6
作者：
Gu XL;Long CX;Sun L;Xie C;Lin X;Cai H
通讯作者：
Cai H