EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers

Abstract

The accumulation of beta-sheet-rich amyloid fibrils or aggregates is a complex, multistep process that is associated with cellular toxicity in a number of human protein misfolding disorders, including Parkinson's and Alzheimer's diseases. It involves the formation of various transient and intransient, on- and off-pathway aggregate species, whose structure, size and cellular toxicity are largely unclear. Here we demonstrate redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers. The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

“…In particular, disorder-to-order transitions upon EGCG binding have been observed for the human salivary proline-rich protein IB5 41 and the dephosphorylated form of -casein 42 . Moreover, EGCG has been shown to affect the aggregation pathway of several amyloidogenic proteins 4,[6][7][8] . These studies also suggest that EGCG binds to the protein backbone, as well as to hydrophilic and hydrophobic side chains.…”

“…The protective effect of EGCG against amyloidosis has been attributed to the formation of off-pathway protein oligomers that prevent fibrillation 6 . The here reported results suggest that formation of these off-pathway species is preceded by a compaction of AS monomers upon EGCG binding.…”

“…Compact conformations might interfere with on-pathway fibrillation in different ways. The compact monomers themselves might not be able to bind to existing -sheet oligomers, thus preventing further elongation of proto-fibrils, and/or they could be sequestered into non-amyloidogenic, oligomeric structures 6 .…”

Aβ(1-42) Assembly in the Presence of scyllo-Inositol Derivatives: Identification of an Oxime Linkage as Important for the Development of Assembly Inhibitors

“…EGCG has been shown to inhibit Aβ(1-42) fibrillization by accelerating oligomer aggregation. 19 The oligomerization profile of EGCG showed a sharp increase in Aβ(1-42) oligomerization at 1:5 peptide-to-compound molar ratio ( Figure S2) while taxifolin showed no change in Aβ(1-42) oligomerization. These results agree with the AFM images of Aβ aggregation, which showed that EGCG significantly alters the fibrillization process while taxifolin does not ( Figure S2).…”

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

“…In EGCG treated flies, however, neurodegeneraton was significantly diminished, indicating that the compound has a protective effect on neurotoxicity in transgenic flies [43]. Intriguingly, EGCG is also a potent inhibitor of α-synuclein and amyloid-β fibrillogenesis, suggesting that it is a generic modulator of protein misfolding and aggregation [44].…”