Modulation of α-synuclein AGE-based cytotoxic aggregation by zinc oxide nanoparticles: a potential therapeutic approach

Abstract

The non-enzymatic post-translational glycation, resulting in advanced glycation end product (AGE) formation, is involved in various central nervous system pathologies like Parkinson's and Alzheimer's diseases. α-Synuclein (αS) containing lysine residues can be glycated by α-dicarbonyl species, like methylglyoxal (MGO), that emerge endogenously from different pathways encompassing amino acid metabolism and the Maillard reaction. MGO and free radical generation are considered key factors in the glycation of proteins. In the face of the AGE-based hazard, the current work aims to investigate the role of zinc oxide nanoparticles (ZnONPs) in the MGO-based glycation of αS. The kinetically driven adsorption of the protein onto the ZnONP surfaces forms agglomerates, termed as flocs. This masks a major fraction of the side chains of glycation-prone amino acids against the MGO-mediated glycation, thereby inhibiting the formation of AGE-induced higher-order cytotoxic aggregates. The cytotoxicity assay confirmed that the flocs formation reduces the overall cytotoxic effect brought about by the glycation of αS. Thus, the findings suggest that ZnONPs act as a platform for the adsorption of the αS monomer, thereby sterically hindering the glycation and AGE-induced higher-order cytotoxic aggregate formation.