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

Abstract

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.

Dietary Antioxidants and Parkinson’s Disease

“…Various research groups have demonstrated that EGCG prevents neurotoxicity associated with α-synuclein [ 91 , 92 , 94 , 95 ]. EGCG chelates metal ions including Cu(II) and Fe(III) to inhibit fibrillation of α-synuclein [ 90 , 93 ]. EGCG (350μM) enhances the formation of stable oligomers (a less-toxic form) thus prevents the accumulation of pathological fibril [ 95 ] EGCG immobilizes α-synuclein and interferes with its oligomerization in biological membranes [ 96 ], thus EGCG helps to maintain membrane integrity [ 95 , 96 ].…”

The Aggregation Conditions Define Whether EGCG is an Inhibitor or Enhancer of α-Synuclein Amyloid Fibril Formation

“…A well-studied polyphenol is epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea. Biochemical studies indicate the neuroprotective action of EGCG, which has been suggested to inhibit the aggregation of a number of amyloidogenic peptides and proteins effectively, including α-synuclein [31][32][33][34][35], amyloid-β (related to AD) [31,36], islet amyloid polypeptide (related to type-II diabetes) [37,38], huntingtin exon 1 (related to Huntington's disease) [39], tau (related to AD and tauopathies) [40], superoxide dismutase (related to amyotrophic lateral sclerosis) [41], prion proteins (related to prion diseases) [42,43], and others. EGCG has the ability to prevent the formation of toxic prefibrillar oligomers, as well as to inhibit amyloid fibril formation and has been proposed to remodel existing amyloid fibrils.…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…Following these results, another study aimed at determining if EGCG had an effect on copper-mediated α-syn aggregation. α-syn overexpressing PC12 cells treated with both copper and EGCG exhibited a decrease in cell loss, in ROS production, and in α-syn accumulation [456]. EGCG was determined to be able to bind copper, thus inhibiting the copper binding on α-syn.…”