This review presents the main properties of hydroxycinnamic acid (HCA) derivatives and their potential application as agents for the prevention and treatment of neurodegenerative diseases. It is partially focused on the successful use of these compounds as inhibitors of amyloidogenic transformation of proteins. Firstly, the prerequisites for the emergence of interest in HCA derivatives, including natural compounds, are described. A separate section is devoted to synthesis and properties of HCA derivatives. Then, the results of molecular modeling of HCA derivatives with prion protein as well as with α-synuclein fibrils are summarized, followed by detailed analysis of the experiments on the effect of natural and synthetic HCA derivatives, as well as structurally similar phenylacetic and benzoic acid derivatives, on the pathological transformation of prion protein and α-synuclein. The ability of HCA derivatives to prevent amyloid transformation of some amyloidogenic proteins, and their presence not only in food products but also as natural metabolites in human blood and tissues, makes them promising for the prevention and treatment of neurodegenerative diseases of amyloid nature.

The review highlights various aspects of the influence of chaperones on amyloid proteins associated with the development of neurodegenerative diseases and includes studies conducted in our laboratory. Different sections of the article are devoted to the role of chaperones in the pathological transformation of alpha-synuclein and the prion protein. Information about the interaction of the chaperonins GroE and TRiC as well as polymer-based artificial chaperones with amyloidogenic proteins is summarized. Particular attention is paid to the effect of blocking chaperones by misfolded and amyloidogenic proteins. It was noted that the accumulation of functionally inactive chaperones blocked by misfolded proteins might cause the formation of amyloid aggregates and prevent the disassembly of fibrillar structures. Moreover, the blocking of chaperones by various forms of amyloid proteins might lead to pathological changes in the vital activity of cells due to the impaired folding of newly synthesized proteins and their subsequent processing. The final section of the article discusses both the little data on the role of gut microbiota in the propagation of synucleinopathies and prion diseases and the possible involvement of the bacterial chaperone GroE in these processes.

The molecular chaperone GroEL is designed to promote protein folding and prevent aggregation. However, the interaction between GroEL and the prion protein, PrP^C, could lead to pathogenic transformation of the latter to the aggregation-prone PrP^Sc form. Here, the molecular basis of the interactions in the GroEL–PrP complex is studied with cryo-EM and molecular dynamics approaches. The obtained cryo-EM structure shows PrP to be bound to several subunits of GroEL at the level of their apical domains. According to MD simulations, the disordered N-domain of PrP forms much more intermolecular contacts with GroEL. Upon binding to the GroEL, the N-domain of PrP begins to form short helices, while the C-domain of PrP exhibits a tendency to unfold its α2-helix. In the absence of the nucleotides in the system, these processes are manifested at the hundred nanoseconds to microsecond timescale.

This review discusses a few examples of specific mechanisms mediating the contribution of the GIT microbiota to the development of amyloid neurodegenerative diseases caused by the pathologic transformation of prion protein, or alpha-synuclein. The effect of the bacterial GroE chaperonin system and phage chaperonins (single-ring OBP and double-ring EL) on prion protein transformation has been described. A number of studies have shown that chaperonins stimulate the formation of cytotoxic amyloid forms of prion protein in an ATP-dependent manner. Moreover, it was found that E. coli cell lysates have a similar effect on prion protein, and the efficiency of amyloid transformation correlates with the content of GroE in cells. Data on the influence of some metabolites synthesized by gut microorganisms on the onset of synucleinopathies, such as Parkinson’s disease, is provided. In particular, the induction of amyloid transformation of alpha-synuclein from intestinal epithelial cells with subsequent prion-like formation of its pathologic forms in nervous tissues featuring microbiota metabolites is described. Possible mechanisms of microbiota influence on the occurrence and development of amyloid neurodegenerative diseases are considered.

Many serious medical conditions are caused by the accumulation of amyloid aggregates in tissues and organs. One of the most well-known amyloidogenic proteins is the prion protein (PrP), which may undergo conformational change between the normal cellular isoform PrPC and the aggregation-prone isoform PrPSc. Elucidation of this conformational transition is necessary for understanding the onset and propagation of prion diseases. However, the flexibility of PrP hinders its research by the experimental methods of protein structure determination. Here, we implement de novo protein modelling and molecular dynamics simulations to predict the interdomain interactions of the full-length PrPC. Our theoretical findings can serve as the basis for mutational analysis and for further studies of the amyloidogenic behavior of the prion protein.