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

Abstract

The amyloid fibril formation by $\alpha$-synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson's disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient aggregation inhibitor of numerous proteins, among them $\alpha$-synuclein. Here we show that this applies only to a small region of relevant parameter space and that under some conditions, EGCG can even accelerate α-synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that contrary to previous reports, EGCG is not able to re-model α-synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of α-synuclein, but the inhibitory action is not robust against various relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterise promising amyloid inhibitors.

Stability matters, too – the thermodynamics of amyloid fibril formation

“…122 Overall the picture shows that such effects may indeed be possible, but signicantly more quantitative and mechanistic research is needed in this area. Aspects that have so far not received enough attention are (1) quantitative evaluation of the effect of the compound on brils, particularly through the use of the latter as seeds, 123 rather than mostly basing the assessment on imaging of the brils; in the latter case results may be confounded by the compound itself. (2) Consideration of chemical reactions that compounds such as EGCG can undergo both by itself and with the protein.…”