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Curcumin prevents formation of polyglutamine aggregates by inhibiting Vps36, a component of the ESCRT-II complex.

ABSTRACT: Small molecules with antioxidative properties have been implicated in amyloid disorders. Curcumin is the active ingredient present in turmeric and known for several biological and medicinal effects. Adequate evidence substantiates the importance of curcumin in Alzheimer's disease and recent evidence suggests its role in Prion and Parkinson's disease. However, contradictory effects have been suggested for Huntington's disease. This difference provided a compelling reason to investigate the effect of curcumin on glutamine-rich (Q-rich) and non-glutamine-rich (non Q-rich) amyloid aggregates in the well established yeast model system. Curcumin significantly inhibited the formation of htt72Q-GFP (a Q-rich) and Het-s-GFP (a non Q-rich) aggregates in yeast. We show that curcumin prevents htt72Q-GFP aggregation by down regulating Vps36, a component of the ESCRT-II (Endosomal sorting complex required for transport). Moreover, curcumin disrupted the htt72Q-GFP aggregates that were pre-formed in yeast and cured the yeast prion, [PSI(+)].

SUBMITTER: Verma M

PROVIDER: S-EPMC3413662 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Curcumin prevents formation of polyglutamine aggregates by inhibiting Vps36, a component of the ESCRT-II complex.

Verma Meenakshi M Sharma Abhishek A Naidu Swarna S Bhadra Ankan Kumar AK Bhadra Ankan Kumar AK Kukreti Ritushree R Taneja Vibha V

PloS one 20120807 8

Small molecules with antioxidative properties have been implicated in amyloid disorders. Curcumin is the active ingredient present in turmeric and known for several biological and medicinal effects. Adequate evidence substantiates the importance of curcumin in Alzheimer's disease and recent evidence suggests its role in Prion and Parkinson's disease. However, contradictory effects have been suggested for Huntington's disease. This difference provided a compelling reason to investigate the effect ...[more]

PMID: 22880132

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Project description:BackgroundProtein misfolding and subsequent aggregation are hallmarks of several human diseases. The cell has a variety of mechanisms for coping with misfolded protein stress, including ubiquitin-mediated protein degradation. In fact, the presence of ubiquitin at protein aggregates is a common feature of protein misfolding diseases. Ubiquitin conjugating enzymes (UBCs) are part of the cascade of enzymes responsible for the regulated attachment of ubiquitin to protein substrates. The specific UBC used during ubiquitination can determine the type of polyubiquitin chain linkage, which in turn plays an important role in determining the fate of the ubiquitinated protein. Thus, UBCs may serve an important role in the cellular response to misfolded proteins and the fate of protein aggregates.ResultsThe Q82 strain of C. elegans harbors a transgene encoding an aggregation prone tract of 82 glutamine residues fused to green fluorescent protein (Q82::GFP) that is expressed in the body wall muscle. When measured with time-lapse microscopy in young larvae, the initial formation of individual Q82::GFP aggregates occurs in approximately 58 minutes. This process is largely unaffected by a mutation in the C. elegans E1 ubiquitin activating enzyme. RNAi of ubc-22, a nematode homolog of E2-25K, resulted in higher pre-aggregation levels of Q82::GFP and a faster initial aggregation rate relative to control. Knockdown of ubc-1 (RAD6 homolog), ubc-13, and uev-1 did not affect the kinetics of initial aggregation. However, RNAi of ubc-13 decreases the rate of secondary growth of the aggregate. This result is consistent with previous findings that aggregates in young adult worms are smaller after ubc-13 RNAi. mCherry::ubiquitin becomes localized to Q82::GFP aggregates during the fourth larval (L4) stage of life, a time point long after most aggregates have formed. FLIP and FRAP analysis indicate that mCherry::ubiquitin is considerably more mobile than Q82::GFP within aggregates.ConclusionsThese data indicate that initial formation of Q82::GFP aggregates in C. elegans is not directly dependent on ubiquitination, but is more likely a spontaneous process driven by biophysical properties in the cytosol such as the concentration of the aggregating species. The effect of ubiquitination appears to be most significant in later, secondary aggregate growth.

Project description:BACKGROUND:Vps25p is the product of yeast gene VPS25 and is found in an endosomal sorting complex required for transport (ESCRT)-II, along with Vps22p and Vps36p. This complex is essential for sorting of ubiquitinated biosynthetic and endosomal cargoes into endosomes. RESULTS:We found that VPS25 is a highly conserved and widely expressed eukaryotic gene, with single orthologs in chromalveolate, excavate, amoebozoan, plant, fungal and metazoan species. Two paralogs were found in Trichomonas vaginalis. An ortholog was strikingly absent from the Encephalitozoon cuniculi genome. Intron positions were analyzed in VPS25 from 36 species. We found evidence for five ancestral VPS25 introns, intron loss, and single instances of intron gain (a Paramecium species) and intron slippage (Theileria species). Processed pseudogenes were identified in four mammalian genomes, with a notable absence in the mouse genome. Two retropseudogenes were found in the chimpanzee genome, one more recently inserted, and one evolving from a common primate ancestor. The amino acid sequences of 119 Vps25 orthologs are aligned, compared with the known secondary structure of yeast Vps25p, and used to carry out phylogenetic analysis. Residues in two amino-terminal PPXY motifs (motif I and II), involved in dimerization of Vps25p and interaction with Vps22p and Vps36p, were closely, but not absolutely conserved. Specifically, motif I was absent in Vps25 homologs of chromalveolates, euglenozoa, and diplomonads. A highly conserved carboxy-terminal lysine was identified, which suggests Vps25 is ubiquitinated. Arginine-83 of yeast Vps25p involved in Vps22p interaction was highly, but not absolutely, conserved. Human tissue expression analysis showed universal expression. CONCLUSION:We have identified 119 orthologs of yeast Vps25p. Expression of mammalian VPS25 in a wide range of tissues, and the presence in a broad range of eukaryotic species, indicates a basic role in eukaryotic cell function. Intron splice site positions were highly conserved across all major eukaryotic species, suggesting an ancestral origin. Amino acid sequence analysis showed the consensus for the amino-terminal proline-rich motifs is P- [WP]-X-[YF] for motif I (when present) and P-P-[FYL]-[FY] for motif II, and that Vps25 may be ubiquitinated.

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Curcumin prevents formation of polyglutamine aggregates by inhibiting Vps36, a component of the ESCRT-II complex.

Publications

Curcumin prevents formation of polyglutamine aggregates by inhibiting Vps36, a component of the ESCRT-II complex.

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