Anti-aggregation Effects of Phenolic Compounds on α-synuclein

The aggregation and deposition of alpha -synuclein (alpha S) are major pathologic features of Parkinson's disease, dementia with Lewy bodies, and other alpha -synucleinopathies. The propagation of alpha S pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate alpha S aggregation and propagation. Based on cumulative evidence that alpha S oligomers are neurotoxic and critical species in the pathogenesis of alpha -synucleinopathies, we and other groups reported that phenolic compounds inhibit alpha S aggregation including oligomerization, thereby ameliorating alpha S oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit alpha S oligomerization and mediate aggregated alpha S-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular alpha S seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-alpha S aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of alpha -synucleinopathies.