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 tiny fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. Dr. Parra-Rivas found that unlike wild-type (WT) α-syn, 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, Dr. Parra-Rivas found that neuronal activity augments Ser129P, which triggers protein-protein interactions 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 facilitates interactions with binding partners. Dr. Parra-Rivas' experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for gene editing therapies. Together with Drs. Madhivanan and Roy he continues investigating the physiological roles of α-synuclein at synapses using CRISPR-based strategies.

Key Points:

• Phosphorylation of α-syn at the Ser129-site (α-syn Ser129P) is a pathologic hallmark of synucleinopathies that is often synonymously associated with disease, but our studies suggest that this post-translational modification has a physiologic role.
• α-syn is widely expressed in synapses throughout the brain, whereas Ser129P is only seen in a subset of brain regions, and this phosphorylation augments the synaptic targeting of α-syn.
• Ser129P facilitates protein-protein interactions at the synapse and functions as a brake on activity-dependent synaptic vesicle recycling.
• Our data reveal a cascade of molecular events by which Ser129P of α-syn regulates synaptic function and offers a new basis for understanding the role of this post-translational modification in pathophysiology.