Curcumin Prevents Aggregation in α-Synuclein by Increasing Reconfiguration Rate

Ahmad, Basir; Lapidus, Lisa J.

doi:10.1074/jbc.m111.325548

Cited by 165 publications

(154 citation statements)

References 25 publications

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“…Moreover, in a proof-of-principle experiment, the effect of curcumin, a previously described known inhibitor of WT αS oligomerization, was checked. [46][47][48] The results further confirmed the effectiveness of this rapid and sensitive cell model in monitoring A53T αS oligomerization affected by different treatments. Also, our cell-based reporter was used to assess the influence of Fe 3 O 4 NPs on aggregation of αS.…”

supporting

confidence: 68%

Investigation of the effects of carbon-based nanomaterials on A53T alpha-synuclein aggregation using a whole-cell recombinant biosensor

Mohammadi¹,

Nikkhah²,

Hosseinkhani³

2017

IJN

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The aggregation of alpha-synuclein (αS), natively unstructured presynaptic protein, is a crucial factor leading to the pathogenesis of Parkinson’s disease (PD) and other related disorders. Recent studies have shown prefibrillar and oligomeric intermediates of αS as toxic to the cells. Herein, split-luciferase complementation assay is used to design a “signal-on” biosensor to monitor oligomerization of A53T αS inside the cells. Then, the effect of carbon-based nanomaterials, such as graphene quantum dots (GQDs) and graphene oxide quantum dots (GOQDs), on A53T αS oligomerization in vitro and in living cells is investigated. In this work, for the first time, it was found that GQDs at a concentration of 0.5 μg/mL can promote A53T αS aggregation by shortening the nucleation process, which is the key rate-determining step of fibrillation, thereby making a signal-on biosensor. While these nanomaterials may cross the blood–brain barrier because of their small sizes, the interaction between αS and GQDs may contribute to PD etiology.

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supporting

confidence: 68%

Investigation of the effects of carbon-based nanomaterials on A53T alpha-synuclein aggregation using a whole-cell recombinant biosensor

Mohammadi¹,

Nikkhah²,

Hosseinkhani³

2017

IJN

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“…However, other protein aggregation inhibitors are active in the presence of thiol reducing agents or are otherwise not associated with protein oxidation or alkylation. For example, curcumin has been reported to increase the reconfiguration rate of ␣-synuclein, such that occupancy of assembly competent conformations is minimized (22,23). This mechanism implies direct but transient interaction between inhibitor and natively unfolded protein monomer.…”

mentioning

confidence: 99%

Structural Determinants of Tau Aggregation Inhibitor Potency

Schafer¹,

Cisek²,

Huseby

et al. 2013

Journal of Biological Chemistry

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Background: Mechanistic insight into small-molecule Tau aggregation inhibitors is needed for their advancement as therapeutic agents. Results: Structure-activity relationship analysis identified polarizability as a common descriptor of inhibitor potency. Conclusion: Flat, highly polarizable ligands stabilize soluble oligomeric complexes at the expense of filamentous aggregates. Significance: The findings suggest a basis for rational improvement of ligand potency, whereas maintaining bioavailability.

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“…However, when k −1 ∼ k bi , then formation of O is rapid. The fast and medium diffusion coefficient regimes have been investigated previously in α-synuclein (26,43,44), but the prion protein exhibits dynamics in all three regimes. After formation of the oligomer, reconfiguration has less impact on subsequent aggregation steps.…”

Section: Discussionmentioning

confidence: 99%

“…However, aggregation is more likely when reconfiguration is about the same rate as bimolecular diffusion. We recently tested this model of aggregation by correlating intramolecular diffusion with aggregation propensity of α-synuclein under a variety solvent conditions, with mutation and with the use of small molecule inhibitors (26,(43)(44)(45).In the present study, we have investigated intramolecular diffusion of the Syrian hamster and rabbit prion proteins, two sequences with very different propensities to aggregate (46-50). Our results show that both prion sequences diffuse rapidly at high denaturants (6 M GdnHCl) and drops dramatically at low denaturant, accompanied by a slight collapse of the polypeptide chain.…”

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confidence: 99%

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Prion protein dynamics before aggregation

Srivastava

Lapidus

2017

Proc. Natl. Acad. Sci. U.S.A.

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Prion diseases, like Alzheimer's disease and Parkinson disease, are rapidly progressive neurodegenerative disorders caused by misfolding followed by aggregation and accumulation of protein deposits in neuronal cells. Here we measure intramolecular polypeptide backbone reconfiguration as a way to understand the molecular basis of prion aggregation. Our hypothesis is that when reconfiguration is either much faster or much slower than bimolecular diffusion, biomolecular association is not stable, but as the reconfiguration rate becomes similar to the rate of biomolecular diffusion, the association is more stable and subsequent aggregation is faster. Using the technique of Trp-Cys contact quenching, we investigate the effects of various conditions on reconfiguration dynamics of the Syrian hamster and rabbit prion proteins. This protein exhibits behavior in all three reconfiguration regimes. We conclude that the hamster prion is prone to aggregation at pH 4.4 because its reconfiguration rate is slow enough to expose hydrophobic residues on the same time scale that bimolecular association occurs, whereas the rabbit sequence avoids aggregation by reconfiguring 10 times faster than the hamster sequence.protein folding | protein aggregation | intramolecular diffusion | prion disease | astemizole P rion disease, also known as transmissible spongiform encephalopathy (TSE) is attributed to misfolding followed by ordered aggregation and accumulation of protein deposits in neuronal cells (1-3). According to the "protein-only" hypothesis, the central event in prion (PrP) pathogenesis is the conformational conversion of the cellular α-helical rich isoform, PrP C , into misfolded β-sheet rich isoform, PrP Sc (3-6). The infectious form PrP Sc is believed to catalyze the conversion of PrP C , thereby permitting transmission between individuals and species (3, 7-10). However, there is very little known about PrP C before ordered aggregation. No putative aggregation precursor structure has been definitively identified; the protein may even be completely unstructured. It is believed that PrP C repeatedly cycles between the cell surface (∼pH 7.0) and endocytic compartment that has a pH as low as 4. 4 (11, 12). Aggregated prion has been isolated from this compartment so it has been suggested that aggregation initiates in late endosomes (13,14). Also, the reduction of the disulfide bridge has been reported to augment misfolding in vitro and may play a significant role in prion pathogenesis (15)(16)(17)(18)(19)(20). However, the physical basis for aggregation of prion, particularly under certain solvent conditions, is still poorly understood.Protein folding is a diffusive search of the unfolded polypeptide chain over the energy landscape in conformational space for a minimum energy state (21). Intramolecular diffusion (diffusion of one part of the chain relative to another) plays a critical role by determining the rate at which an unfolded polypeptide chain finds its native state (22-25). It has been measured for various peptides and pro...

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Curcumin Prevents Aggregation in α-Synuclein by Increasing Reconfiguration Rate

Cited by 165 publications

References 25 publications

Investigation of the effects of carbon-based nanomaterials on A53T alpha-synuclein aggregation using a whole-cell recombinant biosensor

Investigation of the effects of carbon-based nanomaterials on A53T alpha-synuclein aggregation using a whole-cell recombinant biosensor

Structural Determinants of Tau Aggregation Inhibitor Potency

Prion protein dynamics before aggregation

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