Inhibitory effects of gut microbiome–based phenolic compounds on α–synuclein aggregation

Abstract

The aggregation and deposition of α–synuclein (αS) are major pathologic features of Parkinson's disease, dementia with Lewy bodies, and other α–synucleinopathies. The αS aggregation and its propagation play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate them. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α–synucleinopathies, we previously reported that polyphenols such as myricetin inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer–induced cellular and synaptic toxicities.

Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. We recently showed that brain–penetrating polyphenolic acids 3–hydroxybenzoic acid (3–HBA), 3,4–dihydroxybenzoic acid (3,4–diHBA), and 3–hydroxyphenylacetic acid (3–HPPA), which are gut microbiota–based metabolites of dietary polyphenols, had an in vitro ability to inhibit αS oligomerization and mediate αS aggregates–induced neurotoxicity. Additionally, 3–HPPA, 3,4–diHBA, 3–HBA, and 4–HBA significantly attenuated intracellular αS seeding aggregation in a cell–based system. Here, we focus on recent research developments regarding the significance of αS aggregation and anti–αS aggregation effects of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α–synucleinopathies.