Fig. 4

Potential interplay between DOPAL and αSynuclein at pre-synaptic terminals and determinants of DOPAL accumulation. DOPAL accumulation at the pre-synaptic terminals covalently modifies αSyn lysines, reducing αSyn affinity for membrane binding and resulting in synaptic vesicles pools redistribution [38, 41]. αSyn-DOPAL oligomers accumulate and permeabilize synaptic vesicles membrane [41], leading to cytosolic DA release, which is further metabolized into DOPAL by MAO. Also, DOPAL activates AEP (PDB: 4aw9, in the figure), which cleaves αSyn at N103 [76]. Truncated αSyn is more prone to aggregation and stimulates MAO activity. Hence, the result is a positive loop that self amplifies, leading to αSyn aggregation and synapse degeneration. In the figure, the black thin arrows indicate the chemical reactions, while the thicker ones highlight the cellular processes. Among the factors that could lead to DOPAL build-up, the critical hubs are the dysfunction of DA storage in synaptic vesicles, increased rate of DA degradation by MAO and decreased DOPAL detoxification by ALDHs. For each point, the evidences are listed in the figure