EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity
EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity
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DOI：
10.1073/pnas.0910723107
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发表时间：
2010-04-27
影响因子：
11.1
通讯作者：
Wanker, Erich E.
中科院分区：
文献类型：
--
作者：
Bieschke, Jan;Russ, Jenny;Wanker, Erich E.
蛋白质错误折叠和富含β折叠的淀粉样蛋白原纤维或聚集体的形成与包括阿尔茨海默病和帕金森病在内的各种人类疾病中的细胞毒性和衰变有关。最近，我们证明了多酚（-）-表没食子儿茶素没食子酸酯（EGCG）抑制α-突触核蛋白和淀粉样蛋白-β纤维形成。它与天然未折叠的多肽结合，并促进新型非结构化寡聚体的自组装。然而，EGCG是否分解预先形成的淀粉样纤维仍不清楚。在这里，我们表明，表没食子儿茶素没食子酸酯有能力将大的，成熟的α-突触核蛋白和β-淀粉样蛋白原纤维转化为较小的，无定形的蛋白质聚集体，对哺乳动物细胞无毒。机制研究表明，该化合物直接结合到β-折叠丰富的聚集体和介导的构象变化，而不会分解成单体或小的可扩散的低聚物。这些发现表明，表没食子儿茶素没食子酸酯是一种有效的重塑剂的成熟淀粉样纤维。
Protein misfolding and formation of beta-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer's and Parkinson's disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits alpha-synuclein and amyloid-beta fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature alpha-synuclein and amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to beta-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.