Inhibition of α-Synuclein Aggregation by Polyphenols
DOI:
https://doi.org/10.15330/jpnubio.12.87-100Keywords:
α-synuclein, Parkinson’s disease, amyloid fibril, polyphenols.Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder marked by intracellular Lewy bodies, composed mainly of amyloid fibrils formed by α-synuclein (αSyn). Native αSyn is a soluble intrinsically disordered protein, but in PD it misfolds into a pathological β-sheet structure that aggregates, impairs mitochondrial function, triggers inflammation, and ultimately leads to neuronal death. Because αSyn aggregation proceeds through multistep nucleation and rapid fibril elongation, inhibiting this process—particularly by blocking fibril growth at the ends—is a promising therapeutic strategy. This review focuses on polyphenols as inhibitors of αSyn amyloid fibril aggregation. Polyphenols modulate aggregation through diverse mechanisms, including stabilization of monomers, redirection into non-toxic off-pathway oligomers (e.g., EGCG, Resveratrol), disruption of existing fibrils (Baicalein), and covalent modification of αSyn lysine residues (Quercetin, Hydroxytyrosol). Importantly, gut microbiota-derived metabolites of dietary polyphenols (such as 3-HPPA) can cross the blood–brain barrier and strongly attenuate αSyn seeding, underscoring their therapeutic potential in PD.
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