Complex of EGCG with Cu(II) Suppresses Amyloid Aggregation and Cu(II)-Induced Cytotoxicity of α-Synuclein

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 16; p. 2940
• Main Authors: Teng, Yilong, Zhao, Juan, Ding, Lulu, Ding, Yu, Zhou, Ping
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.08.2019; MDPI
• Subjects: alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Alzheimer's disease; Amyloid; Amyloidogenic Proteins - chemistry; Amyloidogenic Proteins - metabolism; Animals; Catechin - analogs & derivatives; Catechin - chemistry; Catechin - pharmacology; Cell Line; Cell viability; complex; Conformation; Copper; Copper - chemistry; Copper - toxicity; Cytotoxicity; EGCG; Epigallocatechin gallate; Fibrillation; Fibrils; Homeostasis; Metal ions; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurotoxicity; Nuclear Magnetic Resonance, Biomolecular; Oxidative Stress; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pheochromocytoma cells; Protected species; Protein Aggregates - drug effects; Protein Aggregation, Pathological - drug therapy; Protein Aggregation, Pathological - metabolism; Proteins; Random coil; Rats; Reactive Oxygen Species - metabolism; Synuclein; α-synuclein; copper; EGCG; Parkinson’s disease; α-synuclein; complex
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24162940

Accumulation of α-synuclein (α-Syn) is a remarkable pathology for Parkinson's disease (PD), therefore clearing it is possibly a promising strategy for treating PD. Aberrant copper (Cu(II)) homeostasis and oxidative stress play critical roles in the abnormal aggregation of α-Syn in the progress of PD. It is reported that the polyphenol (-)-epi-gallocatechin gallate (EGCG) can inhibit α-Syn fibrillation and aggregation, disaggregate α-Syn mature fibrils, as well as protect α-Syn overexpressed-PC12 cells against damage. Also, previous studies have reported that EGCG can chelate many divalent metal ions. What we investigate here is whether EGCG can interfere with the Cu(II) induced fibrillation of α-Syn and protect the cell viability. In this work, on a molecular and cellulaire basis, we demonstrated that EGCG can form a Cu(II)/EGCG complex, leading to the inhibition of Cu(II)-induced conformation transition of α-Syn from random coil to β-sheet, which is a dominant structure in α-Syn fibrils and aggregates. Moreover, we found that the mixture of Cu(II) and EGCG in a molar ratio from 0.5 to 2 can efficiently inhibit this process. Furthermore, we demonstrated that in the α-Syn transduced-PC12 cells, EGCG can inhibit the overexpression and fibrillation of α-Syn in the cells, and reduce Cu(II)-induced reactive oxygen species (ROS), protecting the cells against Cu(II)-mediated toxicity.