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 propagation of αS 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 αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds 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. 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 αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies.
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This work was supported by Grants-in-Aid for Scientific Research (Kakenhi) from the Japan Society for the Promotion of Science (JSPS), under grants JP19K07965 (K.O.) and JP19K11698 (M.T.), and a grant from the Research and Development Grants for Dementia awarded by the Japan Agency for Medical Research and Development (16dk0207021h0001) (K.O.), grant number P50 AT008661-01, from the NCCIH and the ODS (G.M.P.).
Ono, Kenjiro; Tsuji, Mayumi; Yamasaki, Tritia R.; and Pasinetti, Giulio M., "Anti-Aggregation Effects of Phenolic Compounds on α-Synuclein" (2020). Neurology Faculty Publications. 35.