Fig. 5

Effects of αSynuclein dyshomeostasis on synapse functionality. Under physiological conditions, αSyn ensures the correct balance of DA release in the striatum by binding to synaptic vesicles membrane, regulating vesicles mobility and the exocytotic events. However, upon αSyn dyshomeostasis, which includes both αSyn accumulation or its absence, the synaptic vesicles distribution among the different pools and the neurotransmitter release are altered, as demonstrated in the Syn-TKO and the αSyn-OVX mouse models [77, 79, 82,83,84]. Conversely, the DOPAL-αSyn interplay presents an additional level of complexity. Indeed, DOPAL modification of αSyn lysines hinders its association to synaptic vesicles membrane, mimicking a KO-like phenotype [38]. At the same time, DOPAL triggers αSyn aggregation in off-pathway pore-forming oligomers, resulting in synaptic vesicles permeabilization [41]. Furthermore, DOPAL build-up induces synaptic vesicles clustering of the resting pool, resembling the αSyn-overexpressing scenario [41]