(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

Research output: Contribution to journalArticle

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.

LanguageEnglish
Article number6965
JournalScientific Reports
Volume8
DOIs
StatePublished - 3 May 2018

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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, D., Jardim, C., Figueira, I., Almeida, A. F., McDougall, G. J., Stewart, D., ... Santos, C. N. (2018). (Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis. Scientific Reports, 8, [6965]. DOI: 10.1038/s41598-018-25118-z
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.
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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.",
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Macedo, D, Jardim, C, Figueira, I, Almeida, AF, McDougall, GJ, Stewart, D, Yuste, JE, Tomás-Barberán, FA, Tenreiro, S, Outeiro, TF & Santos, CN 2018, '(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis' Scientific Reports, vol. 8, 6965. DOI: 10.1038/s41598-018-25118-z

(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, 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.

AU - Stewart,Derek

AU - Yuste,Jose E.

AU - Tomás-Barberán,Francisco A.

AU - Tenreiro,Sandra

AU - Outeiro,Tiago F.

AU - Santos,Cláudia N.

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Macedo D, Jardim C, Figueira I, Almeida AF, McDougall GJ, Stewart D et al. (Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis. Scientific Reports. 2018 May 3;8. 6965. Available from, DOI: 10.1038/s41598-018-25118-z