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Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy
Translational Neurodegeneration ( IF 10.8 ) Pub Date : 2019-06-15 , DOI: 10.1186/s40035-019-0159-7
Jia-Zhen Wu 1, 2 , Mustafa Ardah 3 , Caroline Haikal 4 , Alexander Svanbergsson 4 , Meike Diepenbroek 4 , Nishant N Vaikath 4, 5 , Wen Li 4 , Zhan-You Wang 6 , Tiago F Outeiro 7, 8 , Omar M El-Agnaf 5 , Jia-Yi Li 1, 4, 6
Affiliation  

Progressive accumulation of α-synuclein is a key step in the pathological development of Parkinson’s disease. Impaired protein degradation and increased levels of α-synuclein may trigger a pathological aggregation in vitro and in vivo. The chaperone-mediated autophagy (CMA) pathway is involved in the intracellular degradation processes of α-synuclein. Dysfunction of the CMA pathway impairs α-synuclein degradation and causes cytotoxicity. In the present study, we investigated the effects on the CMA pathway and α-synuclein aggregation using bioactive ingredients (Dihydromyricetin (DHM) and Salvianolic acid B (Sal B)) extracted from natural medicinal plants. In both cell-free and cellular models of α-synuclein aggregation, after administration of DHM and Sal B, we observed significant inhibition of α-synuclein accumulation and aggregation. Cells were co-transfected with a C-terminal modified α-synuclein (SynT) and synphilin-1, and then treated with DHM (10 μM) and Sal B (50 μM) 16 hours after transfection; levels of α-synuclein aggregation decreased significantly (68% for DHM and 75% for Sal B). Concomitantly, we detected increased levels of LAMP-1 (a marker of lysosomal homeostasis) and LAMP-2A (a key marker of CMA). Immunofluorescence analyses showed increased colocalization between LAMP-1 and LAMP-2A with α-synuclein inclusions after treatment with DHM and Sal B. We also found increased levels of LAMP-1 and LAMP-2A both in vitro and in vivo, along with decreased levels of α-synuclein. Moreover, DHM and Sal B treatments exhibited anti-inflammatory activities, preventing astroglia- and microglia-mediated neuroinflammation in BAC-α-syn-GFP transgenic mice. Our data indicate that DHM and Sal B are effective in modulating α-synuclein accumulation and aggregate formation and augmenting activation of CMA, holding potential for the treatment of Parkinson’s disease.

中文翻译:

二氢杨梅素和丹酚酸 B 抑制 α-突触核蛋白聚集并增强伴侣介导的自噬

α-突触核蛋白的逐渐积累是帕金森病病理发展的关键步骤。蛋白质降解受损和 α-突触核蛋白水平升高可能在体外和体内引发病理性聚集。伴侣介导的自噬 (CMA) 途径参与 α-突触核蛋白的细胞内降解过程。CMA 通路的功能障碍会损害 α-突触核蛋白降解并导致细胞毒性。在本研究中,我们使用从天然药用植物中提取的生物活性成分(二氢杨梅素 (DHM) 和丹酚酸 B (Sal B))研究了对 CMA 途径和 α-突触核蛋白聚集的影响。在α-突触核蛋白聚集的无细胞和细胞模型中,在施用 DHM 和 Sal B 后,我们观察到对 α-突触核蛋白积累和聚集的显着抑制。细胞用 C 端修饰的 α-synuclein (SynT) 和 synphilin-1 共转染,然后在转染 16 小时后用 DHM (10 μM) 和 Sal B (50 μM) 处理;α-突触核蛋白聚集水平显着降低(DHM 为 68%,Sal B 为 75%)。同时,我们检测到 LAMP-1(溶酶体稳态标志物)和 LAMP-2A(CMA 的关键标志物)水平升高。免疫荧光分析显示,在用 DHM 和 Sal B 处理后,LAMP-1 和 LAMP-2A 与 α-突触核蛋白包涵体之间的共定位增加。我们还发现 LAMP-1 和 LAMP-2A 在体外和体内的水平增加,同时水平降低α-突触核蛋白。此外,DHM 和 Sal B 治疗表现出抗炎活性,可防止 BAC-α-syn-GFP 转基因小鼠中星形胶质细胞和小胶质细胞介导的神经炎症。
更新日期:2020-04-22
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