Enhancing the Astrocytic Clearance of Extracellular α-Synuclein Aggregates by Ginkgolides Attenuates Neural Cell Injury
Enhancing the Astrocytic Clearance of Extracellular α-Synuclein Aggregates by Ginkgolides Attenuates Neural Cell Injury
复制标题
银杏内酯增强星形胶质细胞对细胞外 α-突触核蛋白聚集体的清除，减轻神经细胞损伤
DOI：
10.1007/s10571-019-00696-2
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发表时间：
2019-10-01
影响因子：
4
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Hua, Jun;Yin, Nuo;Hu, Gang
聚集形式的α-突触核蛋白（α-Syn）的积累与帕金森病（PD）的发病机制相关，并且聚集的α-Syn的有效清除代表了PD治疗中的潜在方法。星形胶质细胞是脑中数量最多的胶质细胞，在PD状态下对脑功能的支持起着至关重要的作用。在本研究中，我们证明了培养的原代星形胶质细胞吞噬和降解细胞外聚集的重组人α-Syn。同时，我们观察到蛋白酶体抑制剂MG 132和自噬抑制剂3-甲基腺嘌呤（3 MA）可以阻断星形胶质细胞对α-Syn的清除。我们进一步表明，银杏内酯B（GB）和白果内酯（BB）处理后，细胞内α-Syn减少，MG 132和3 MA逆转了这种减少。更重要的是，GB和BB减少由α-Syn刺激的星形胶质细胞条件培养基诱导的对神经元的间接神经毒性。我们首次发现星形胶质细胞可以通过蛋白酶体和自噬途径吞噬和降解α-Syn聚集体，并进一步表明GB和BB增强星形胶质细胞对α-Syn的清除，这为我们了解未来PD的新治疗提供了新的思路。
The accumulation of aggregated forms of the alpha-Synuclein (alpha-Syn) is associated with the pathogenesis of Parkinson's disease (PD), and the efficient clearance of aggregated alpha-Syn represents a potential approach in PD therapy. Astrocytes are the most numerous glia cells in the brain and play an essential role in supporting brain functions in PD state. In the present study, we demonstrated that cultured primary astrocytes engulfed and degraded extracellular aggregated recombinant human alpha-Syn. Meanwhile, we observed that the clearance of alpha-Syn by astrocytes was abolished by proteasome inhibitor MG132 and autophagy inhibitor 3-methyladenine (3MA). We further showed that intracellular alpha-Syn was reduced after ginkgolide B (GB) and bilobalide (BB) treatment, and the decrease was reversed by MG132 and 3MA. More importantly, GB and BB reduced indirect neurotoxicity to neurons induced by alpha-Syn-stimulated astrocytic conditioned medium. Together, we firstly find that astrocytes can engulf and degrade alpha-Syn aggregates via the proteasome and autophagy pathways, and further show that GB and BB enhance astrocytic clearance of alpha-Syn, which gives us an insight into the novel therapy for PD in future.