EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

TLDR

Protein misfolding into β‑sheet‑rich amyloid fibrils is linked to cellular toxicity in diseases such as Alzheimer’s and Parkinson’s, yet it was unclear whether EGCG could disassemble preformed fibrils. EGCG binds directly to β‑sheet‑rich aggregates and induces a conformational change without disassembling them into monomers or small oligomers. EGCG inhibits α‑synuclein and amyloid‑β fibrillogenesis, binds unfolded polypeptides to form new unstructured oligomers, and remodels mature fibrils into smaller, non‑toxic amorphous aggregates, demonstrating its potency as a remodeling agent.

Abstract

Protein misfolding and formation of β-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer’s and Parkinson’s disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits α-synuclein and amyloid-β fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.