(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis

Diana Macedo,Tiago F Outeiro,Francisco A Tomás-Barberán,Derek Stewart,A Filipa Almeida,Jose E Yuste,Inês Figueira,Cláudia N Santos,Sandra Tenreiro,Gordon J Mcdougall,Carolina Jardim

doi:10.1038/s41598-018-25118-z

Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative disease associated with the misfolding and aggregation of alpha-synuclein (aSyn). The molecular underpinnings of PD are still obscure, but nutrition may play an important role in the prevention, onset, and disease progression. Dietary (poly)phenols revert and prevent age-related cognitive decline and neurodegeneration in model systems. However, only limited attempts were made to evaluate the impact of digestion on the bioactivities of (poly)phenols and determine their mechanisms of action. This constitutes a challenge for the development of (poly)phenol-based nutritional therapies. Here, we subjected (poly)phenols from Arbutus unedo to in vitro digestion and tested the products in cell models of PD based on the cytotoxicity of aSyn. The (poly)phenol-digested metabolites from A. unedo leaves (LPDMs) effectively counteracted aSyn and H2O2 toxicity in yeast and human cells, improving viability by reducing aSyn aggregation and inducing its clearance. In addition, LPDMs modulated pathways associated with aSyn toxicity, such as oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial impairment, and SIR2 expression. Overall, LPDMs reduced aSyn toxicity, enhanced the efficiency of ER-associated protein degradation by the proteasome and autophagy, and reduced oxidative stress. In total, our study opens novel avenues for the exploitation of (poly)phenols in nutrition and health.

Highlights

Several studies support the beneficial effects ofphenols and their bioavailability and accumulation even in the brain[8,9]
The excessive accumulation of unfolded proteins and oxidative stress that are typical in Parkinson’s disease (PD), result in the failure of the endoplasmic reticulum (ER) to cope with the excess of protein load, a process denominated by ER stress[14,15]
phenol-digested metabolites (PDMs) were able to suppress toxicity induced by aSyn expression, while cells treated with LPDMs grew to control cells (Fig. 1A)

Summary

Introduction

Several studies support the beneficial effects of (poly)phenols and their bioavailability and accumulation even in the brain[8,9]. In response to ER stress, cells activate the unfolded protein response (UPR)[14,15,16], leading to the transcription of genes related with protein homeostasis, including chaperones, and protein degradation and secretion pathways[14]. Macroautophagy, hereafter designated as autophagy, is initiated in response to ER stress caused by misfolded proteins, via ER-activated autophagy (ERAA)[16,17], which induces a partial UPR and a calcium-mediated signalling cascade. ERAA is a degradation pathway and serves the function of mitigating ER stress and suppressing cell death, as ERAD16. The clearance of soluble aSyn can occur both via the UPS and chaperone-mediated autophagy (CMA)[18]. We previously showed that (poly)phenols can protect against aSyn toxicity by promoting its clearance trough autophagy and by modulating aSyn fibrillation[24]. The potential of these (poly)phenols in the context of neurodegeneration has not been explored

Methods

Results

Conclusion