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

Diana Macedo1,2,3, Carolina Jardim1,2, Inês Figueira1,2

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Dietary polyphenols, digested from Arbutus unedo leaves, protect against Parkinson's disease (PD) by reducing alpha-synuclein (aSyn) toxicity and aggregation in cellular models.

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Area of Science:

  • Neuroscience
  • Nutritional Science
  • Biochemistry

Background:

  • Parkinson's disease (PD) involves alpha-synuclein (aSyn) misfolding and aggregation.
  • Nutrition, particularly dietary polyphenols, may influence PD onset and progression.
  • The impact of digestion on polyphenol bioactivity for PD therapies is understudied.

Purpose of the Study:

  • To investigate the effects of in vitro digested Arbutus unedo polyphenols on aSyn-induced cytotoxicity.
  • To elucidate the mechanisms by which digested polyphenols counteract aSyn toxicity in cellular models.

Main Methods:

  • Subjected Arbutus unedo polyphenols to in vitro digestion.
  • Tested digested metabolites (LPDMs) in yeast and human cell models of PD.
  • Assessed cell viability, aSyn aggregation, aSyn clearance, oxidative stress, ER stress, mitochondrial function, and SIR2 expression.

Main Results:

  • Digested polyphenols (LPDMs) effectively counteracted aSyn and H2O2 toxicity, enhancing cell viability.
  • LPDMs reduced aSyn aggregation and promoted its clearance.
  • LPDMs modulated key pathways including oxidative stress, ER stress, mitochondrial impairment, and SIR2 expression, enhancing protein degradation via proteasome and autophagy.

Conclusions:

  • Digested Arbutus unedo polyphenols show significant neuroprotective effects against aSyn toxicity.
  • These findings support the development of polyphenol-based nutritional strategies for Parkinson's disease prevention and management.
  • The study highlights the importance of considering digestion in evaluating polyphenol efficacy for health applications.