VAMP2 is a R-SNARE protein essential for synaptic vesicle fusion and neurotransmitter release. As a major component of the SNARE complex on synaptic vesicles, VAMP2 mediates exocytosis through direct interaction with target membrane components and facilitates rapid vesicle recycling 1. VAMP2 functions beyond basic membrane fusion: it directly binds α-synuclein's C-terminal region through electrostatic interactions in its juxtamembrane domain, orchestrating α-synuclein phase separation and protecting it from pathological aggregation into amyloid fibrils 2. This protective mechanism is physiologically relevant, as VAMP2-mediated α-synuclein interactions promote synaptic vesicle clustering and SNARE complex assembly 21. VAMP2-dependent exocytosis extends beyond classical neurotransmission. In specialized cells like tanycytes, VAMP2 mediates exocytosis of signaling molecules (VEGFA) critical for thermoregulation and appetite control 3. NG2 glia similarly employ VAMP2-containing vesicles for GABAergic signaling 4. Diseased states implicate VAMP2 dysfunction: phosphorylated tau in Alzheimer's disease directly interacts with VAMP2 5, potentially disrupting synaptic vesicle dynamics. The protein's involvement in synucleinopathies suggests VAMP2 dysregulation may contribute to Parkinson's disease pathogenesis through compromised α-synuclein regulation 2. These findings position VAMP2 as a critical nexus between normal synaptic physiology and neurodegenerative disease mechanisms.