Metal chelator EGCG attenuates Fe(III)-inducedconformational transition of alpha-synuclein and protects AS-PC12 cells against Fe(III)-induced death
Metal chelator EGCG attenuates Fe(III)-inducedconformational transition of alpha-synuclein and protects AS-PC12 cells against Fe(III)-induced death
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金属螯合剂 EGCG 减弱 Fe(III) 诱导的 α-突触核蛋白构象转变，并保护 AS-PC12 细胞免遭 Fe(III) 诱导的死亡
DOI：
10.1111/jnc.14142
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发表时间：
2017
影响因子：
4.7
通讯作者：
Ping Zhou
中科院分区：
文献类型：
--
作者：
Juan Zhao;Lihui Xu;Qingnan Liang;Qing Sun;Congheng Chen;Yuan Zhang;Yu Ding;Ping Zhou
α-突触核蛋白（α-synuclein，AS）的纤维化和聚集，沿着从无规卷曲到β-折叠的构象转变，是帕金森病（Parkinson's disease，PD）发生发展的关键步骤。铁在脑内的蓄积可能导致AS的纤维化。然而，（-）-表没食子儿茶素没食子酸酯（EGCG）可以穿透血脑屏障，螯合金属离子，并抑制淀粉样蛋白的纤维化。因此，EGCG有必要研究其治愈淀粉样蛋白相关疾病的潜力。在目前的工作中，我们试图在分子和细胞水平上研究EGCG对Fe（III）诱导的AS纤维化的影响。我们证明Fe（III）与AS的Tyr和Ala的氨基残基相互作用，然后加速AS的纤维化，并增加AS转导的-PC 12细胞（AS-PC 12细胞）中的细胞内活性氧（ROS）。然而，EGCG通过螯合Fe（III）显着抑制这一过程，并保护AS-PC 12细胞免受ROS和富含β折叠的AS原纤维诱导的毒性。这些发现提供了有用的信息，表没食子儿茶素没食子酸酯可能是一个有前途的药物，以预防和治疗神经退行性疾病。
The fibrillation and aggregation of α‐synuclein (AS), along with the conformational transition from random coil to β‐sheet, are the critical steps in the development of Parkinson's disease (PD). It is acknowledged that iron accumulation in the brain may lead to the fibrillation of AS. However, (‐)‐epigallocatechin gallate (EGCG) can penetrate the blood–brain barrier, chelate metal ions, and inhibit the fibrillation of amyloid proteins. Therefore, EGCG is warranted to be investigated for its potential to cure amyloid‐related diseases. In the present work, we sought to study the effects of EGCG on Fe(III)‐induced fibrillation of AS on both molecular and cellular levels. We demonstrate that Fe(III) interacts with the amino residue of Tyr and Ala of AS, then accelerates the fibrillation of AS, and increases intracellular reactive oxygen species (ROS) in the AS transduced‐PC12 cells (AS‐PC12 cells). However, EGCG significantly inhibits this process by chelating Fe(III) and protects AS‐PC12 cells against the toxicity induced by ROS and β‐sheet‐enriched AS fibrils. These findings yield useful information that EGCG might be a promising drug to prevent and treat the neurodegenerative diseases.