Insight into the Effect of Methylglyoxal on the Conformation, Function, and Aggregation Propensity of α-Synuclein

It is well-known that people suffering from hyperglycemia have a higher propensity to develop Parkinson's disease (PD). One of the most plausible mechanisms linking these two pathologies is the glycation of neuronal proteins and the pathological consequences of it. alpha-Synuclein, a key component in PD, can be glycated at its fifteen lysine. In fact, the end products of this process have been detected on aggregated alpha-synuclein isolated from in vivo. However, the consequences of glycation are not entirely clear, which are of crucial importance to understand the mechanism underlying the connection between diabetes and PD. To better clarify this, we have here examined how methylglyoxal (the most important carbonyl compound found in the cytoplasm) affects the conformation and aggregation propensity of alpha-synuclein, as well as its ability to cluster and fuse synaptic-like vesicles. The obtained data prove that methylglyoxal induces the Lys-Lys crosslinking through the formation of MOLD. However, this does not have a remarkable effect on the averaged conformational ensemble of alpha-synuclein, although it completely depletes its native propensity to form soluble oligomers and insoluble amyloid fibrils. Moreover, methylglyoxal has a disrupting effect on the ability of alpha-synuclein to bind, cluster and fusion synaptic-like vesicles. Methylglyoxal reacts with alpha-synuclein (alpha S) by forming a heterogeneous mixture of reaction products on specific Lys. Among them highlights the 2-ammonio-6-[1-(5-ammonio-6-oxido-6-oxohexyl)-5-methylimidazolium-3-yl] hexanoate (MOLD), which crosslinks two Lys. The formation of these MG-derived AGEs had a scarce effect on the averaged conformational ensemble of alpha S, but they completely depleted its native propensity to aggregate and its ability to bind, cluster and fusion synaptic-like vesicles. image