Neurodegenerative diseases are associated with accumulation of amyloid-type protein misfolding products. Prion protein (PrP) is known for its ability to aggregate into soluble oligomers that in turn associate into amyloid fibrils. Preventing the formation of these infective and neurotoxic entities represents a viable strategy to control prion diseases. Numerous attempts to find dietary compounds with anti-prion properties have been made; however, the most promising agent found so far was curcumin, which is poorly soluble and merely bioavailable. In the present work, we identify 3,4-dimethoxycinnamic acid (DMCA) which is a bioavailable coffee component as a perspective anti-prion compound. 3,4-Dimethoxycinnamic acid was found to bind potently to prion protein with a Kd of 405 nM. An in vitro study of DMCA effect on PrP oligomerization and fibrillization was undertaken using isothermal titration calorimetry (ITC), dynamic light scattering (DLS) and circular dichroism (CD) methodologies. We demonstrated that DMCA affects PrP oligomer formation reducing the oligomer content by 30-40%, and enhancing SH-SY5Y cell viability treated with prion oligomers. Molecular docking studies allowed to suggest a site where DMCA is able to bind stabilizing PrP tertiary structure. We suggest that DMCA is a perspective dietary compound for prophylaxis of neurodegenerative diseases that needs further research. Copyright © 2017 John Wiley & Sons, Ltd.
The possibility of inhibition of chaperonin functional activity by amyloid proteins was studied. It was found that the ovine prion protein PrP as well as its oligomeric and fibrillar forms are capable of binding with the chaperonin GroEL. Besides, GroEL was shown to promote amyloid aggregation of the monomeric and oligomeric PrP as well as PrP fibrils. The monomeric PrP was shown to inhibit the GroEL-assisted reactivation of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The oligomers of PrP decelerate the GroEL-assisted reactivation of GAPDH, and PrP fibrils did not affect this process. The chaperonin GroEL is capable of interacting with GAPDH and different PrP forms simultaneously. A possible role of the inhibition of chaperonins by amyloid proteins in the misfolding of the enzymes involved in cell metabolism and in progression of neurodegenerative diseases of amyloid nature is discussed.
Background: Information about the stimulation by glycation of the amyloid transformation of proteins, including beta-casein, is not well defined. On the one hand, it is possible to detect signs characteristic of amyloid structures (primarily changes in the fluorescence of thioflavin T (ThT) by various indirect methods, and on the other hand, using direct methods, primarily electron microscopy, it is not possible to reveal characteristic beta-casein amyloid fibrils. In the present work, we investigated the thermal aggregation of glycated beta-casein, paying particular attention to the effect of ThT on the formation of various aggregates, including unusual spiral structures, first discovered in this work. Methods: Glycated beta-casein transformation was studied by the use of ThT fluorescence, fluorescence microscopy and transmission electron microscopy. Results: This study reports an appearance of unusual spiral-like structures in aggregates formed by glycated beta-casein in the presence of ThT. Different incubation conditionsglycation agent, temperature, pH, incubation time and concentration of protein and modifier were characterized, but only glycation by 0.2 M glucose for 2 days at 37°C leads to formation of spiral structures. The beta-casein content of these structures was confirmed by ninhydrin reaction, as well as immunohistochemical staining of spiral aggregates. Interaction of glycated beta-casein with ThT leads to a 3.5-fold increase in the intensity of its fluorescence, which is about 2 times less than for dye, bound to beta-sheet structures of amyloid proteins. ThT affects the size of the particles formed by glycated beta-casein and also stimulates heat-induced aggregation not only for glucose modification but also with a relatively rapid modification by methylglyoxal. Reduction with sodium cyanoborohydride has no significant effect on the ability of ThT to interact with beta-casein and alter its properties. Conclusion: The results suggest that such interactions of ThT molecule with glycated proteins should be taken into account while using it as an indicator for amyloid structures and as a potential agent for prevention and treatment of amyloidosis.
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