Figure 4.

The presynaptic exo-endocytotic cycle regulating neurotransmitter release is specifically affected in α-Syn-related synaptopathies. Upon an incoming action potential, calcium (Ca²⁺) channels become permeable to Ca²⁺ entry in the presynaptic terminal. This activates a molecular machinery including the SNARE complex proteins that recruit synaptic vesicles (SV) from the proximal resting and recycling (RP) pools via trafficking and tethering to form the readily releasable pool (RRP). After docking and priming, RRP vesicles undergo SNARE-mediated membrane fusion at the active zone (AZ, shaded area), ultimately leading to neurotransmitter (NT) release into the synaptic cleft. After exocytosis, the SV membrane is retrieved to the presynaptic terminal via endocytosis, to be filled with NT (NT uptake) and re-enter the exo-endocytotic cycle, thereby granting the neuron its ability to sustain high firing rates. PSD95, postsynaptic density protein-95.