Anti-aggregation Effects of Phenolic Compounds on α-synuclein.

Kenjiro Ono,Mayumi Tsuji,Tritia R Yamasaki,Giulio M Pasinetti

doi:10.3390/molecules25102444

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 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.

Highlights

Parkinson’s disease (PD) is the most common type of parkinsonism, a term reflecting a group of neurological disorders that cause PD–like movement problems such as rigidity, slowness, and tremor.More than six million individuals worldwide have PD [1]
We demonstrated that phenolic compounds such as myricetin (Myr), Cur, rosmarinic acid (RA), nordihydroguaiaretic acid (NDGA), and ferulic acid (FA) inhibit the formation of αS fibrils and destabilize preformed fibrils [27]
Using the A53T mutant αS Drosophila model of PD, we further investigated the effects of 3-hydroxybenzoic acid (3-HBA), 3,4-diHBA, and 3-HPPA on modulating PD pathologic phenotypes, in vivo, by monitoring locomotive functions using a negative geotaxis behavior assay in adult flies [124]

Summary

Introduction

Parkinson’s disease (PD) is the most common type of parkinsonism, a term reflecting a group of neurological disorders that cause PD–like movement problems such as rigidity, slowness, and tremor. It has been reported that EGCG exerts protective effects against αS oligomer-induced membrane disruption and cytotoxicity by facilitating fibril formation and eliminating toxic αS oligomers [35]. These results suggest that phenolic compounds prevent the occurrence of αS aggregation, thereby reducing the neurotoxicity of αS oligomers. A single point mutation can significantly alter the distribution of fibrillar polymorphs of αS, suggesting that differences in the clinical phenotypes of familial PD could be associated with changes to the mechanism of formation and the particular structural characteristics of the aggregates [59]

Toxicity of αS Oligomers

Antioxidant Properties of Phenolic Compounds

Inhibition of αS Fibrillization by Phenolic Compounds

Inhibition of αS Oligomerization by Phenolic Compounds

Conclusions and Future