Gottfried Schatz Research Center for Cell Signaling, Metabolism and Ageing, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
BioTechMed-Graz, 8010 Graz, Austria.
Cells. 2022 Feb 9;11(4):592. doi: 10.3390/cells11040592.
Millions of people worldwide are affected by neurodegenerative diseases (NDs), and to date, no effective treatment has been reported. The hallmark of these diseases is the formation of pathological aggregates and fibrils in neural cells. Many studies have reported that catechins, polyphenolic compounds found in a variety of plants, can directly interact with amyloidogenic proteins, prevent the formation of toxic aggregates, and in turn play neuroprotective roles. Besides harboring amyloidogenic domains, several proteins involved in NDs possess arginine-glycine/arginine-glycine-glycine (RG/RGG) regions that contribute to the formation of protein condensates. Here, we aimed to assess whether epigallocatechin gallate (EGCG) can play a role in neuroprotection via direct interaction with such RG/RGG regions. We show that EGCG directly binds to the RG/RGG region of fused in sarcoma (FUS) and that arginine methylation enhances this interaction. Unexpectedly, we found that low micromolar amounts of EGCG were sufficient to restore RNA-dependent condensate formation of methylated FUS, whereas, in the absence of EGCG, no phase separation could be observed. Our data provide new mechanistic roles of EGCG in the regulation of phase separation of RG/RGG-containing proteins, which will promote understanding of the intricate function of EGCG in cells.
全世界有数百万的人受到神经退行性疾病（NDs）的影响，迄今为止，还没有有效的治疗方法被报道。这些疾病的特征是在神经细胞中形成病理性聚集体和纤维。许多研究报告称，儿茶素是一种存在于多种植物中的多酚化合物，可以直接与淀粉样蛋白相互作用，防止有毒聚集体的形成，从而发挥神经保护作用。除了含有淀粉样蛋白结构域外，几种参与 NDs 的蛋白质还具有精氨酸-甘氨酸/精氨酸-甘氨酸-甘氨酸（RG/RGG）区域，有助于形成蛋白质凝聚物。在这里，我们旨在评估表没食子儿茶素没食子酸酯（EGCG）是否可以通过与 RG/RGG 区域的直接相互作用来发挥神经保护作用。我们表明，EGCG 直接与肉瘤融合（FUS）的 RG/RGG 区域结合，并且精氨酸甲基化增强了这种相互作用。出乎意料的是，我们发现低微摩尔浓度的 EGCG 足以恢复甲基化 FUS 的 RNA 依赖性凝聚物形成，而在没有 EGCG 的情况下，无法观察到相分离。我们的数据提供了 EGCG 在 RG/RGG 含蛋白相分离调节中的新的机制作用，这将促进对 EGCG 在细胞中复杂功能的理解。
