Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India 400076.
ACS Chem Neurosci. 2013 Mar 20;4(3):393-407. doi: 10.1021/cn3001203. Epub 2012 Dec 17.
In human beings, Parkinson's disease (PD) is associated with the oligomerization and amyloid formation of α-synuclein (α-Syn). The polyphenolic Asian food ingredient curcumin has proven to be effective against a wide range of human diseases including cancers and neurological disorders. While curcumin has been shown to significantly reduce cell toxicity of α-Syn aggregates, its mechanism of action remains unexplored. Here, using a series of biophysical techniques, we demonstrate that curcumin reduces toxicity by binding to preformed oligomers and fibrils and altering their hydrophobic surface exposure. Further, our fluorescence and two-dimensional nuclear magnetic resonance (2D-NMR) data indicate that curcumin does not bind to monomeric α-Syn but binds specifically to oligomeric intermediates. The degree of curcumin binding correlates with the extent of α-Syn oligomerization, suggesting that the ordered structure of protein is required for effective curcumin binding. The acceleration of aggregation by curcumin may decrease the population of toxic oligomeric intermediates of α-Syn. Collectively; our results suggest that curcumin and related polyphenolic compounds can be pursued as candidate drug targets for treatment of PD and other neurological diseases.
在人类中，帕金森病（PD）与α-突触核蛋白（α-Syn）的寡聚化和淀粉样形成有关。多酚类亚洲食品成分姜黄素已被证明对包括癌症和神经疾病在内的多种人类疾病有效。虽然姜黄素已被证明能显著降低α-Syn 聚集物的细胞毒性，但它的作用机制仍未被探索。在这里，我们使用一系列生物物理技术证明，姜黄素通过与预形成的寡聚体和原纤维结合并改变其疏水面暴露来降低毒性。此外，我们的荧光和二维核磁共振（2D-NMR）数据表明，姜黄素不与单体α-Syn 结合，而是特异性结合于寡聚体中间体。姜黄素的结合程度与α-Syn 寡聚化的程度相关，这表明蛋白质的有序结构是有效结合姜黄素所必需的。姜黄素对聚集的加速作用可能会降低α-Syn 的有毒寡聚体中间产物的数量。总的来说，我们的结果表明，姜黄素和相关多酚类化合物可以作为治疗 PD 和其他神经疾病的候选药物靶点进行研究。
