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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 <jats:italic>Arbutus unedo<\/jats:italic> to <jats:italic>in vitro<\/jats:italic> digestion and tested the products in cell models of PD based on the cytotoxicity of aSyn. The (poly)phenol-digested metabolites from <jats:italic>A. unedo<\/jats:italic> leaves (LPDMs) effectively counteracted aSyn and H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> 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 <jats:italic>SIR2<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41598-018-25118-z","type":"journal-article","created":{"date-parts":[[2018,4,27]],"date-time":"2018-04-27T09:36:24Z","timestamp":1524821784000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1798-3408","authenticated-orcid":false,"given":"Diana","family":"Macedo","sequence":"first","affiliation":[]},{"given":"Carolina","family":"Jardim","sequence":"additional","affiliation":[]},{"given":"In\u00eas","family":"Figueira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-0710","authenticated-orcid":false,"given":"A. Filipa","family":"Almeida","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-0124","authenticated-orcid":false,"given":"Gordon J.","family":"McDougall","sequence":"additional","affiliation":[]},{"given":"Derek","family":"Stewart","sequence":"additional","affiliation":[]},{"given":"Jose E.","family":"Yuste","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0790-1739","authenticated-orcid":false,"given":"Francisco A.","family":"Tom\u00e1s-Barber\u00e1n","sequence":"additional","affiliation":[]},{"given":"Sandra","family":"Tenreiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1679-1727","authenticated-orcid":false,"given":"Tiago F.","family":"Outeiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5809-1924","authenticated-orcid":false,"given":"Cl\u00e1udia N.","family":"Santos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2018,5,3]]},"reference":[{"key":"25118_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.3389\/fphar.2014.00147","volume":"5","author":"P Mecocci","year":"2014","unstructured":"Mecocci, P., Tinarelli, C., Schulz, R. J. & Polidori, M. C. Nutraceuticals in cognitive impairment and Alzheimer\u2019s disease. Frontiers in Pharmacology 5, 147, https:\/\/doi.org\/10.3389\/fphar.2014.00147 (2014).","journal-title":"Frontiers in Pharmacology"},{"key":"25118_CR2","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1089\/ars.2012.4581","volume":"18","author":"D Del Rio","year":"2013","unstructured":"Del Rio, D. et al. Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal 18, 1818\u20131892, https:\/\/doi.org\/10.1089\/ars.2012.4581 (2013).","journal-title":"Antioxid Redox Signal"},{"key":"25118_CR3","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.jep.2007.11.029","volume":"116","author":"S Afkir","year":"2008","unstructured":"Afkir, S. et al. Arbutus unedo prevents cardiovascular and morphological alterations in L-NAME-induced hypertensive rats - Part 1: Cardiovascular and renal hemodynamic effects of Arbutus unedo in L-NAME-induced hypertensive rats. Journal of Ethnopharmacology 116, 288\u2013295, https:\/\/doi.org\/10.1016\/j.jep.2007.11.029 (2008).","journal-title":"Journal of Ethnopharmacology"},{"key":"25118_CR4","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1080\/14786410500161205","volume":"20","author":"EJ Carcache-Blanco","year":"2006","unstructured":"Carcache-Blanco, E. J. et al. Potential cancer chemopreventive agents from Arbutus unedo. Natural Product Research 20, 327\u2013334, https:\/\/doi.org\/10.1080\/14786410500161205 (2006).","journal-title":"Natural Product Research"},{"key":"25118_CR5","doi-asserted-by":"publisher","first-page":"25","DOI":"10.2174\/1389450003349380","volume":"1","author":"FV DeFeudis","year":"2000","unstructured":"DeFeudis, F. V. & Drieu, K. 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