Fig. 1. Membrane interactions of αS in functional and pathological contexts. Under physiological conditions (left side of the synapse), αS has been shown to interact with SVs and promote their clustering^18–20 into SV pools forming at the synaptic termini^17,22–24 (a). In addition, in the active zone αS has been associated to a chaperone role of the SNARE formation^15,16 (b). αS also binds to mitochondria where it has been associated with the mitigation of oxidative stress (c). Under aggregation-prone conditions (right “dark side” of the synapse), αS is believed to aggregate first in amorphous early aggregates (d). Subsequently, these evolve into pre-fibrillar oligomeric species (e) that diffuse in the cellular milieu and establish aberrant interactions affecting the cellular viability.¹ The toxic oligomers are able to bind and disrupt the plasma membrane (f), causing calcium influx and metal dishomeostasis, and to disrupt the mitochondrial integrity (g) by provoking the release of cytochrome C. These oligomers ultimately evolve into mature fibrils, which have been shown to be the major constituents of Lewy bodies. Several literature evidences indicate that αS fibrils are considerably less neurotoxic than oligomeric species,¹ however, mature amyloids can still act as pathogenic agents by acting as reservoirs of toxic oligomers that are released as a result of fragmentation.¹³⁹.