Glycation of α-synuclein hampers its binding to synaptic-like vesicles and its driving effect on their fusion

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders affecting the worldwide population. One of its hallmarks is the intraneuronal accumulation of insoluble Lewy bodies (LBs), which cause the death of dopaminergic neurons. alpha-Synuclein (alpha S) is the main component of these LBs and in them, it commonly contains non-enzymatic post-translational modifications, such as those resulting from its reaction with reactive carbonyl species arising as side products of the intraneuronal glycolysis (mainly methylglyoxal). Consequently, lysines of the alpha S found in LBs of diabetic individuals are usually carboxyethylated. A precise comprehension of the effect of N-epsilon-(carboxyethyl)lysine (CEL) on the aggregation of alpha S and on its physiological function becomes crucial to fully understand the molecular mechanisms underlying the development of diabetes-induced PD. Consequently, we have here used a synthetic alpha S where all its Lys have been replaced by CEL moieties (alpha S-CEL), and we have studied how these modifications could impact on the neurotransmission mechanism. This study allows us to describe how the non-enzymatic glycosylation (glycation) affects the function of a protein like alpha S, involved in the pathogenesis of PD. CEL decreases the ability of alpha S to bind micelles, although the micelle-bound fraction of alpha S-CEL still displays an alpha-helical fold resembling that of the lipid-bound alpha S. However, CEL completely abolishes the affinity of alpha S towards synaptic-like vesicles and, consequently, it hampers its physiological function as a catalyst of the clustering and the fusion of the synaptic vesicles.

Automated summary

Parkinson's disease is a prevalent neurodegenerative disorder characterized by the accumulation of insoluble Lewy bodies in neurons, leading to neuronal death. The main component of these Lewy bodies, alpha-synuclein, undergoes non-enzymatic post-translational modifications, which affect its aggregation and physiological function. Understanding these modifications is crucial for better understanding the mechanisms underlying diabetes-induced Parkinson's disease.