Catechins, NMR, Huntington’s disease, protein aggregation modulation

Abstract

Catechins, a subclass of flavonoids widely found in plants and plant-based foods and beverages such as wine and tea, not only exhibit significant antioxidant properties [1], as extensively documented in the literature, but can also inhibit amyloid protein aggregation [2], a key process implicated in the onset of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s.

Observations of kinetics profiles suggested that amyloid fibrils formation could be modelled by a sigmoidal function, reflecting the fact that this process consists primarily of two stages: nucleation and elongation.

Detailed studies on this kind of polymerization have shown that the mass concentration of polymer in solution frequently increases more rapidly than predicted by the classical model, suggesting the extension including secondary nucleation pathways, which can contribute to the increase in the number of polymers in addition to that produced by the straightforward homogeneous nucleation [3]. More specifically, monomer-dependent secondary nucleation [4] and monomer-independent secondary nucleation in the form of fragmentation [5] emerged as a key factor in the propagation.

Our study aims to elucidate the mechanisms by which flavonoids, starting with (+)-catechin (2R,3S) —the most common catechin isomer— modulate the aggregation kinetics of Huntingtin protein exon 1 (the portion of the protein directly involved in the aggregation) encoding CAG/polyglutamine repeat expansion. To achieve this, we integrated NMR spectroscopy with computational analysis. Building on existing literature, we have developed a comprehensive mathematical framework that incorporates primary nucleation, elongation, and secondary nucleation stages of protein aggregation, incorporating additionally the presence of a generic binding molecule by considering all interaction pathways through which it may influence aggregation kinetics. By fitting this model to NMR experimental data, we seek to determine the specific stage within the aggregation cascade where catechin exerts its influence, thereby shedding light on its potential anti-amyloid mechanism of action.

References

[1] Pietta, Pier-G. (2000). Journal of Natural Products, 63(7), 1035-1042.

[2] Martinez Pomier, K., Ahmed, R., Melacini, G. (2020). Molecules, 25(16).

[3] Cohen, S.I., Vendruscolo, M., Welland, M.E., Dobson, C.M., Terentjev, E.M., Knowles, T.P. (2011). J Chem Phys,135(6):065105

[4] Cohen, S.I., Vendruscolo, M., Dobson, C.M., Knowles, T.P. (2011). J Chem Phys.135(6):065106

[5] Cohen, S.I., Vendruscolo, M., Dobson, C.M., Knowles, T.P. (2011). J Chem Phys.135(6):065107