The polyphenol quercetin protects from glucotoxicity depending on the aggresome in Caenorhabditis elegans

  • Mehtap Civelek
  • Sandra Flory
  • Hedda Meloh
  • Elena Fitzenberger
  • Uwe WenzelEmail author
Original Contribution



Impaired proteostasis, i.e., protein homeostasis, is considered as a consequence of high-glucose exposure and is associated with reduced survival. The previous studies demonstrated that the polyphenol quercetin can protect from glucotoxicity. The aim of the present study was to unravel the contribution of the aggresome, sequestering potentially cytotoxic aggregates and also acting as a staging center for eventual autophagic clearance from the cell.


Knockdown of the aggresome-relevant genes dnc-1 and ubql-1 was achieved in stress-sensitive mev-1 mutants of the nematode Caenorhabditis elegans by RNA interference (RNAi). Survival assay was conducted under heat stress at 37 °C, protein aggregation using ProteoStat® and chymotrypsin-like proteasomal activity according to the cleavage of a fluorogenic peptide substrate.


Survival was reduced by knockdown of ubql-1 and even more by knockdown of dnc-1 which both were not further reduced by addition of glucose. The rescue of survival due to quercetin in glucose-exposed nematodes was completely prevented under RNAi versus ubql-1 or dnc-1. Both knockdowns caused an increase of aggregated protein and prevented the reduction of aggregated protein caused by quercetin in glucose-exposed animals. Finally, the knockdown of ubql-1 and dnc-1 blocked the increase of proteasomal activity achieved by quercetin in glucose-treated nematodes.


The study provides evidence that quercetin protects C. elegans from glucotoxicity through the activation of the aggresome, thereby, quercetin prevents the aggregation and functional loss of proteins, which is typically caused by enhanced glucose concentrations.


Aggresome Proteasome Caenorhabditis elegans Glucotoxicity Quercetin Survival 


C. elegans

Caenorhabditis elegans


Dynactin complex component


Double-stranded RNA

E. coli

Escherichia coli




RNA interference


Reactive oxygen species


Sequestosome-related 1


Ubiquilin 1


Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Preuss HG (1997) Effects of glucose/insulin perturbations on aging and chronic disorders of aging: the evidence. J Am Coll Nutr 16(5):397–403. CrossRefGoogle Scholar
  2. 2.
    Monnier L, Colette C, Owens D (2012) The glycemic triumvirate and diabetic complications: is the whole greater than the sum of its component parts? Diabetes Res Clin Pract 95(3):303–311. CrossRefGoogle Scholar
  3. 3.
    Chevion M, Berenshtein E, Stadtman ER (2000) Human studies related to protein oxidation: protein carbonyl content as a marker of damage. Free Radic Res 33:S99–S108Google Scholar
  4. 4.
    Beal MF (2002) Oxidatively modified proteins in aging and disease. Free Radic Biol Med 32(9):797–803CrossRefGoogle Scholar
  5. 5.
    Puddu A, Viviani GL (2011) Advanced glycation endproducts and diabetes. Beyond vascular complications. Endocr Metab Immune Disord Drug Targets 11(2):132–140CrossRefGoogle Scholar
  6. 6.
    Semba RD, Nicklett EJ, Ferrucci L (2010) Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci 65(9):963–975. CrossRefGoogle Scholar
  7. 7.
    Mooradian AD, Thurman JE (1999) Glucotoxicity: potential mechanisms. Clin Geriatr Med 15(2):255CrossRefGoogle Scholar
  8. 8.
    Fitzenberger E, Boll M, Wenzel U (2013) Impairment of the proteasome is crucial for glucose-induced lifespan reduction in the mev-1 mutant of Caenorhabditis elegans. Biochim Biophys Acta 1832(4):565–573. CrossRefGoogle Scholar
  9. 9.
    Fitzenberger E, Deusing DJ, Marx C et al (2014) The polyphenol quercetin protects the mev-1 mutant of Caenorhabditis elegans from glucose-induced reduction of survival under heat-stress depending on SIR-2.1, DAF-12, and proteasomal activity. Mol Nutr Food Res 58(5):984–994. CrossRefGoogle Scholar
  10. 10.
    Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10(2):205–215. CrossRefGoogle Scholar
  11. 11.
    Civelek M, Mehrkens J-F, Carstens N-M et al (2018) Inhibition of mitophagy decreases survival of Caenorhabditis elegans by increasing protein aggregation. Mol Cell Biochem. Google Scholar
  12. 12.
    Hyttinen JMT, Amadio M, Viiri J et al (2014) Clearance of misfolded and aggregated proteins by aggrephagy and implications for aggregation diseases. Ageing Res Rev 18:16–28. CrossRefGoogle Scholar
  13. 13.
    Rodriguez-Gonzalez A, Lin T, Ikeda AK et al (2008) Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation. Cancer Res 68(8):2557–2560. CrossRefGoogle Scholar
  14. 14.
    Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77(1):71–94Google Scholar
  15. 15.
    Stiernagle T (2006) Maintenance of C. elegans. WormBook. Google Scholar
  16. 16.
    Lehner B, Tischler J, Fraser AG (2006) RNAi screens in Caenorhabditis elegans in a 96-well liquid format and their application to the systematic identification of genetic interactions. Nat Protoc 1(3):1617–1620. CrossRefGoogle Scholar
  17. 17.
    Timmons L, Court DL, Fire A (2001) Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263(1–2):103–112CrossRefGoogle Scholar
  18. 18.
    Gill MS, Olsen A, Sampayo JN et al (2003) An automated high-throughput assay for survival of the nematode Caenorhabditis elegans. Free Radic Biol Med 35(6):558–565. CrossRefGoogle Scholar
  19. 19.
    Caccamo A, Ferreira E, Branca C et al (2017) p62 improves AD-like pathology by increasing autophagy. Mol Psychiatry 22(6):865–873. CrossRefGoogle Scholar
  20. 20.
    Chen Z, Fu Q, Shen B et al (2014) Enhanced p62 expression triggers concomitant autophagy and apoptosis in a rat chronic spinal cord compression model. Mol Med Rep 9(6):2091–2096. CrossRefGoogle Scholar
  21. 21.
    Cabe M, Rademacher DJ, Karlsson AB et al (2018) PB1 and UBA domains of p62 are essential for aggresome-like induced structure formation. Biochem Biophys Res Commun 503(4):2306–2311. CrossRefGoogle Scholar
  22. 22.
    Corchero JL (2016) Eukaryotic aggresomes: from a model of conformational diseases to an emerging type of immobilized biocatalyzers. Appl Microbiol Biotechnol 100(2):559–569. CrossRefGoogle Scholar
  23. 23.
    Chiti F, Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu Rev Biochem 86:27–68. CrossRefGoogle Scholar
  24. 24.
    Hecker M, Wagner AH (2018) Role of protein carbonylation in diabetes. J Inherit Metab Dis 41(1):29–38. CrossRefGoogle Scholar
  25. 25.
    Scior A, Juenemann K, Kirstein J (2016) Cellular strategies to cope with protein aggregation. Essays Biochem 60(2):153–161. CrossRefGoogle Scholar
  26. 26.
    Rousseau A, Bertolotti A (2018) Regulation of proteasome assembly and activity in health and disease. Nat Rev Mol Cell Biol. Google Scholar
  27. 27.
    Lamark T, Svenning S, Johansen T (2017) Regulation of selective autophagy: the p62/SQSTM1 paradigm. Essays Biochem 61(6):609–624. CrossRefGoogle Scholar
  28. 28.
    Kravtsova-Ivantsiv Y, Sommer T, Ciechanover A (2013) The lysine48-based polyubiquitin chain proteasomal signal: not a single child anymore. Angew Chem Int Ed Engl 52(1):192–198. CrossRefGoogle Scholar
  29. 29.
    Regitz C, Dußling LM, Wenzel U (2014) Amyloid-beta (Aβ142)-induced paralysis in Caenorhabditis elegans is inhibited by the polyphenol quercetin through activation of protein degradation pathways. Mol Nutr Food Res 58(10):1931–1940. CrossRefGoogle Scholar
  30. 30.
    Olzmann JA, Li L, Chin LS (2008) Aggresome formation and neurodegenerative diseases: therapeutic implications. Curr Med Chem 15(1):47–60CrossRefGoogle Scholar
  31. 31.
    Kawaguchi Y, Kovacs JJ, McLaurin A et al (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115(6):727–738. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mehtap Civelek
    • 1
  • Sandra Flory
    • 1
  • Hedda Meloh
    • 1
  • Elena Fitzenberger
    • 1
  • Uwe Wenzel
    • 1
    Email author
  1. 1.Interdisciplinary Research CenterJustus-Liebig-University of GiessenGiessenGermany

Personalised recommendations