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

Abstract

[eng] Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders afecting the worldwide population. One of its hallmarks is the intraneuronal accumulation of insoluble Lewy bodies (LBs), which cause the death of dopaminergic neurons. α-Synuclein (αS) is the main component of these LBs and in them, it commonly contains non-enzymatic post translational modifcations, 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 αS found in LBs of diabetic individuals are usually carboxyethylated. A precise comprehension of the efect of Nε-(carboxyethyl)lysine (CEL) on the aggregation of αS and on its physiological function becomes crucial to fully understand the molecular mechanisms underlying the develop ment of diabetes-induced PD. Consequently, we have here used a synthetic αS where all its Lys have been replaced by CEL moieties (αS-CEL), and we have studied how these modifcations could impact on the neurotransmission mechanism. This study allows us to describe how the non-enzymatic glycosylation (glycation) afects the function of a protein like αS, involved in the pathogenesis of PD. CEL decreases the ability of αS to bind micelles, although the micelle-bound fraction of αS-CEL still displays an α-helical fold resembling that of the lipid-bound αS. However, CEL completely abolishes the afnity of αS towards synaptic-like vesicles and, consequently, it hampers its physiological function as a catalyst of the clustering and the fusion of the synaptic vesicles