Epigallocatechin-3-gallate and related phenol compounds redirect the amyloidogenic aggregation pathway of ataxin-3 towards non-toxic aggregates and prevent toxicity in neural cells and Caenorhabditis elegans animal model
Epigallocatechin-3-gallate and related phenol compounds redirect the amyloidogenic aggregation pathway of ataxin-3 towards non-toxic aggregates and prevent toxicity in neural cells and Caenorhabditis elegans animal model
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DOI：
10.1093/hmg/ddx211
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发表时间：
2017-09
影响因子：
3.5
通讯作者：
C. Visentin;F. Pellistri;A. Natalello;J. Vertemara;Marcella Bonanomi;E. Gatta;A. Penco;A. Relini;L. De Gioia;C. Airoldi;M. Regonesi;P. Tortora
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文献类型：
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作者：
C. Visentin;F. Pellistri;A. Natalello;J. Vertemara;Marcella Bonanomi;E. Gatta;A. Penco;A. Relini;L. De Gioia;C. Airoldi;M. Regonesi;P. Tortora
蛋白ataxin-3 （ATX3）在其聚谷氨酰胺拉伸超过临界阈值时触发淀粉样蛋白相关的神经退行性疾病。我们以前证明了多酚表没食子儿茶素-3-没食子酸酯（EGCG）可以将全长扩展ATX3 （ATX3- q55）的淀粉样蛋白聚集重定向为无毒、可溶、抗sds的聚集体。在这里，我们表征了其他相关的酚化合物，尽管尺寸较小，即(-)-表没食子儿茶素没食子酸酯（EGC）和没食子酸（GA）。我们分析了ATX3-Q55和n端球形Josephin结构域（JD）的聚集模式，通过FTIR和AFM评估了可溶性蛋白的时间过程，以及在存在和不存在上述化合物的情况下其结构特征。它们都将聚集模式重新定向为可溶的、抗sds的聚集体。他们还阻止了ATX3-Q55中有序侧链氢键的出现，这是多聚糖相关淀粉样蛋白的标志。对JD的分子对接分析突出了三个相互作用的区域，包括中心的、容易聚集的区域。这三种化合物都与它们各自结合，尽管模式不同。这可能解释了它们阻止淀粉样蛋白形成的能力。饱和转移差核磁共振实验也证实了EGCG和EGC与JD单体的结合。ATX3-Q55与三种化合物中的任何一种预先孵育都可以阻止其钙流介导的神经细胞毒性。最后，在表达扩增ATX3的转基因秀丽隐杆线虫菌株中，所有酚类物质都显著降低了毒性。总的来说，我们的研究结果表明，这三种多酚的作用方式基本相似。然而，由于其结构简单，化学稳定性高，GA可能更适合于抗淀粉样蛋白治疗。
The protein ataxin-3 (ATX3) triggers an amyloid-related neurodegenerative disease when its polyglutamine stretch is expanded beyond a critical threshold. We formerly demonstrated that the polyphenol epigallocatechin-3-gallate (EGCG) could redirect amyloid aggregation of a full-length, expanded ATX3 (ATX3-Q55) towards non-toxic, soluble, SDS-resistant aggregates. Here, we have characterized other related phenol compounds, although smaller in size, i.e. (-)-epigallocatechin gallate (EGC), and gallic acid (GA). We analysed the aggregation pattern of ATX3-Q55 and of the N-terminal globular Josephin domain (JD) by assessing the time course of the soluble protein, as well its structural features by FTIR and AFM, in the presence and the absence of the mentioned compounds. All of them redirected the aggregation pattern towards soluble, SDS-resistant aggregates. They also prevented the appearance of ordered side-chain hydrogen bonding in ATX3-Q55, which is the hallmark of polyQ-related amyloids. Molecular docking analyses on the JD highlighted three interacting regions, including the central, aggregation-prone one. All three compounds bound to each of them, although with different patterns. This might account for their capability to prevent amyloidogenesis. Saturation transfer difference NMR experiments also confirmed EGCG and EGC binding to monomeric JD. ATX3-Q55 pre-incubation with any of the three compounds prevented its calcium-influx-mediated cytotoxicity towards neural cells. Finally, all the phenols significantly reduced toxicity in a transgenic Caenorhabditis elegans strain expressing an expanded ATX3. Overall, our results show that the three polyphenols act in a substantially similar manner. GA, however, might be more suitable for antiamyloid treatments due to its simpler structure and higher chemical stability.