Glycation of alpha-synuclein enhances aggregation and neuroinflammatory responses

Abstract

The risk of developing Parkinsons disease (PD) is elevated in people with type 2 diabetes, but the precise molecular pathways underlying this connection are still unclear. One hypothesis is that glycation, a non-enzymatic family of reactions between glycating agents, such as reducing sugars or reactive dicarbonyls, and specific amino acids, such as lysines and arginines, may alter proteostasis and trigger pathological alterations. Glycation of alpha-synuclein (aSyn), a central player in PD pathology, causes profound changes in the aggregation process of aSyn. Methylglyoxal (MGO), a strong glycating agent, induces the formation of pathological inclusions enriched in phosphorylated aSyn on serine 129 (pS129). In addition, we found that neuroinflammatory responses are enhanced by MGO-mediated aSyn glycation. Using novel polyclonal antibodies developed towards specific MGO-glycated aSyn residues, we confirmed the occurrence of glycated aSyn both in vitro as well as in animal and in human brain tissue. In total, our findings shed light into the interplay between glycation, PD, and type 2 diabetes, potentially paving the way for the development of novel therapeutic strategies targeting these intertwined conditions.