Presynaptic Functions of α-Synuclein: Regulating Synaptic Vesicle Dynamics and Neurotransmission with Insights into β- and γ-Synucleins (A Narrative Review)

The synuclein family, comprising α-, β-, and γ-synucleins, consists of highly conserved, intrinsically disordered proteins sharing substantial structural homology and exhibiting multifunctional roles in membrane interactions, vesicle trafficking, lipid homeostasis, and cellular signalling. Synucleins are enriched at presynaptic terminals, where they regulate synaptic vesicle dynamics and neurotransmission by contributing to vesicle clustering, trafficking, and the availability of vesicles for release. Aberrant expression, misfolding, and aggregation of synucleins are associated with several human diseases, particularly neurodegenerative disorders and certain cancers, highlighting their biological and clinical relevance. The primary aim of this review was to provide a focused overview of current knowledge regarding the physiological presynaptic functions of synucleins. By concentrating on this relatively underexplored aspect of synuclein biology, we sought to highlight their roles in synaptic transmission and presynaptic regulation, thereby complementing the extensive literature devoted to their pathological significance. Here, the recent findings on the contributions of α-, β-, and γ-synucleins to synaptic vesicle organization, trafficking and neurotransmitter release were summarized, and their emerging roles in maintaining presynaptic homeostasis were discussed. In addition, we consider how disruption of these physiological functions may contribute to synaptic dysfunction and the development of disease.