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Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn—thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development. • Native α-syn serine-129 phosphorylation is seen in discrete brain regions • Preventing α-syn serine-129 phosphorylation blocks activity-dependent α-syn functions • Neuronal activity augments α-syn serine-129 phosphorylation in cells and in vivo • α-syn serine-129 phosphorylation triggers protein-protein interactions at synapses Phosphorylation of α-synuclein at the serine-129 site is an established pathologic hallmark of Parkinson's disease and related "synucleinopathies," but new findings from Parra-Rivas et al. suggest a physiologic role for this post-translational modification in triggering α-synuclein function by facilitating protein-protein interactions at synapses. [ABSTRACT FROM AUTHOR]