title: Resveratrol reduces amyloid-beta (Aβ₁₋₄₂)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans.
abstract: OBJECTIVE
  Resveratrol is a polyphenol present in red wine for which the capability of directly interfering with the hallmark of Alzheimer's disease (AD), i.e. toxic β-amyloid protein (Aβ) aggregation, has been shown recently. Since the stimulation of proteostasis could explain reduced Aβ-aggregation, we searched for proteostasis targets of resveratrol.
  
  
  METHODS
  The transgenic Caenorhabditis elegans strain CL2006, expressing Aβ1-42 under control of a muscle-specific promoter and responding to Aβ-toxicity with paralysis, was used as a model. Target identification was accomplished through specific knockdowns of proteostasis genes by RNA interference. Effects of resveratrol on protein aggregation were identified using ProteoStat(®) Detection Reagent, and activation of proteasomal degradation by resveratrol was finally proven using a specific fluorogenic peptide substrate.
  
  
  RESULTS
  Resveratrol at a concentration of 100 µM caused a 40 % decrease in paralysis. UBL-5 involved in unfolded protein response (UPR) in mitochondria proved to be necessary for the prevention of Aβ-toxicity by resveratrol. Also XBP-1, which represents an endoplasmic reticulum-resident factor involved in UPR, was identified to be necessary for the effects of resveratrol. Regarding protein degradation pathways, the inhibition of macroautophagy and chaperone-mediated autophagy prevented resveratrol from reducing paralysis as did the inhibition of proteasomal degradation. Finally, resveratrol reduced the amount of lysosomes, suggesting increased flux of proteins through the autophagy pathways and activated proteasomal degradation.
  
  
  CONCLUSIONS
  Resveratrol reduces the Aβ-induced toxicity in a C. elegans model of AD by targeting specific proteins involved in proteostasis and thereby reduces the amount of aggregated Aβ.
authors: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
authors: Charlotte
authors: C
authors: Regitz
authors: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
authors: Elena
authors: E
authors: Fitzenberger
authors: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
authors: Friederike Luise
authors: FL
authors: Mahn
authors: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
authors: Lisa Marie
authors: LM
authors: Dußling
authors: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany. uwe.wenzel@ernaehrung.uni-giessen.de.
authors: Uwe
authors: U
authors: Wenzel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010243:Paralysis / Q000139:chemically induced / Q000188:drug therapy*; D010446:Peptide Fragments / Q000009:adverse effects*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000139:chemically induced / Q000188:drug therapy; D034622:RNA Interference; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D010446:Peptide Fragments; D013267:Stilbenes; D014452:Ubiquitins; C515527:Ubl-5 protein, C elegans; C548541:XBP-1 protein, C elegans; C075222:amyloid beta-protein (1-42); D046988:Proteasome Endopeptidase Complex; D000077185:Resveratrol
keywords: Amyloid-β peptide; Autophagy; Caenorhabditis elegans; Proteasome; Resveratrol; Unfolded protein response