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

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

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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.

Original languageEnglish
Article number6965
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 3 May 2018

Fingerprint

alpha-Synuclein
Phenol
Phenols
Parkinson Disease
Digestion
Oxidative Stress
Endoplasmic Reticulum-Associated Degradation
Endoplasmic Reticulum Stress
Autophagy
Proteasome Endopeptidase Complex
Neurodegenerative Diseases
Proteolysis
Disease Progression
Cell Survival
Yeasts
Health

Cite this

Macedo, Diana ; Jardim, Carolina ; Figueira, Inês ; Almeida, A. Filipa ; McDougall, Gordon J. ; Stewart, Derek ; Yuste, Jose E. ; Tomás-Barberán, Francisco A. ; Tenreiro, Sandra ; Outeiro, Tiago F. ; Santos, Cláudia N. / (Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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title = "(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis",
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.",
author = "Diana Macedo and Carolina Jardim and In{\^e}s Figueira and Almeida, {A. Filipa} and McDougall, {Gordon J.} and Derek Stewart and Yuste, {Jose E.} and Tom{\'a}s-Barber{\'a}n, {Francisco A.} and Sandra Tenreiro and Outeiro, {Tiago F.} and Santos, {Cl{\'a}udia N.}",
note = "info:eu-repo/grantAgreement/FCT/SFRH/SFRH{\%}2FBD{\%}2F73429{\%}2F2010/PT# info:eu-repo/grantAgreement/FCT/5876/147260/PT# info:eu-repo/grantAgreement/WT//019407# info:eu-repo/grantAgreement/FCT/SFRH/SFRH{\%}2FBD{\%}2F86584{\%}2F2012/PT# info:eu-repo/grantAgreement/WT//019407# info:eu-repo/grantAgreement/FCT/SFRH/SFRH{\%}2FBPD{\%}2F35767{\%}2F2007/PT# We acknowledge Rita Ramos for support with qRT-PCR and Regina Menezes for the selection of primers; Antonio Temudo and Ana M. Nascimento for imaging support; The IMM-JLA Flow Cytometry Facility. We also thank Prof. Kuninori Suzuki (Tokyo Institute of Technology, Yokohama, Japan) for the 2xmCherry-ATG8 plasmid. TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain. This work was supported by Fundacao para a Ciencia e Tecnologia [iNOVA4Health: UID/Multi/04462/2013, SFRH/BD/73429/2010 and IMM/BI/78-2017 to DM, SFRH/BD/86584/2012 to IF, IF/01097/2013 to CNS, SFRH/BPD/35767/2007 and SFRH/BPD/101646/2014 to ST]. BacHBerry FP7 KBBE-2013-7 613793 to CNS, DM and CJ, Marie Curie International Reintegration Grant and an EMBO Installation Grant to TFO. TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain. The author(s) would like to acknowledge the STSM to AFA and networking support by the COST Action FA 1403 POSITIVe (Interindividual variation in responseto consumption of plant food bioactives and determinants involved), supported by COST (European Cooperation in Science and Technology).",
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(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis. / Macedo, Diana; Jardim, Carolina; Figueira, Inês; Almeida, A. Filipa; McDougall, Gordon J.; Stewart, Derek; Yuste, Jose E.; Tomás-Barberán, Francisco A.; Tenreiro, Sandra; Outeiro, Tiago F.; Santos, Cláudia N.

In: Scientific Reports, Vol. 8, No. 1, 6965, 03.05.2018.

Research output: Contribution to journalArticle

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AU - Macedo, Diana

AU - Jardim, Carolina

AU - Figueira, Inês

AU - Almeida, A. Filipa

AU - McDougall, Gordon J.

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AU - Outeiro, Tiago F.

AU - Santos, Cláudia N.

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