Synaptic vesicle architecture modulates α-synuclein conformation and pathogenic transitions in Parkinson's disease.

α-Synuclein (α-Syn) is a presynaptic protein implicated in the regulation of synaptic vesicle (SV) organization, soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly, and neurotransmitter release through reversible interactions with curved lipid membranes. Increasing evidence indicates that α-Syn functions as a curvature-sensitive membrane adaptor whose N-terminal amphipathic helices selectively recognize the nanoscale architecture of SVs, thereby promoting vesicle tethering, clustering, and membrane fusion dynamics essential for synaptic transmission. Recent structural and biophysical studies demonstrate that SVs act as catalytic platforms in which membrane curvature, lipid packing defects, molecular crowding, and local physicochemical conditions determine whether α-Syn remains membrane-bound or transitions into pathogenic assemblies. Post-translational modifications, including phosphorylation, nitration, acetylation, and ubiquitination, dynamically regulate α-Syn conformation, membrane engagement, proteostatic turnover, aggregation propensity, and intracellular localization by modulating its structural plasticity and interactions with synaptic membranes. These modifications can alter electrostatic interactions, destabilize amphipathic helices, and shift α-Syn from functional membrane-associated states toward soluble oligomeric and amyloidogenic species. Aging further exacerbates these transitions through alterations in SV lipid composition, membrane fluidity, oxidative membrane damage, impaired proteostasis, and defective vesicle trafficking, thereby destabilizing α-Syn-membrane interactions. The present review discusses how membrane remodeling, vesicle lipid composition, post-translational modifications, protein conformational dynamics, and aging collectively regulate α-Syn phase behavior, membrane binding, and pathological aggregation at the presynaptic terminal. Integrating structural biology, lipidomics, proteomics, and live-cell imaging approaches will identify mechanistic transitions linking physiological membrane engagement to neurodegenerative synucleinopathies and reveal therapeutic opportunities for preventing synaptic dysfunction, toxic condensate formation, and neurodegeneration in Parkinson's disease and related disorders associated with pathological α-Syn aggregation.