α-Synuclein Drives SNARE-Dependent Tubular Remodeling of Vesicles.

α-Synuclein (α-syn) disrupts synaptic vesicle architecture in Parkinson's disease (PD), yet the underlying mechanisms remain unclear. Here, we identify a previously unrecognized phenomenon in which α-syn (≥20 μM) rapidly induces SNARE-dependent tubular protrusions on highly curved small unilamellar vesicles (∼45 nm in diameter). This process requires functional v- and t-SNAREs, as neither v-SNARE nor t-SNARE alone, nor predocked SNARE complexes or CDV-treated SNARE liposomes, support tubulation. Notably, the familial PD-associated mutations A30P and E46K enhance tubule formation, whereas A53T exhibits minimal activity. Disrupting the α-syn-VAMP2 interaction abolishes tubulation, directly linking this interface to vesicle remodeling. Tubule formation increases with α-syn concentration, impairs SNARE-mediated membrane fusion, and significantly modulates α-syn liquid-liquid phase separation (LLPS), underscoring its pathological relevance. These findings reveal a novel mechanism by which α-syn remodels vesicle architecture, providing deeper insights into synaptic dysfunction in PD.