Serine-129 phosphorylation of α-synuclein is a trigger for physiologic protein-protein interactions and synaptic function

Parra-Rivas, L. A.; Madhivanan, K.; Wang, L.; Boyer, N. P.; Prakashchand, D. D.; Aulston, B. D.; Pizzo, D. P.; Branes-Guerrero, K.; Tang, Y.; Das, U.; Scott, D. A.; Rangamani, P.; Roy, S.

doi:10.1101/2022.12.22.521485

bioRxiv · 10.1101/2022.12.22.521485

Serine-129 phosphorylation of α-synuclein is a trigger for physiologic protein-protein interactions and synaptic function

Parra-Rivas, L. A.·Madhivanan, K.·Wang, L.·Boyer, N. P.·Prakashchand, D. D.·Aulston, B. D.·Pizzo, D. P.·Branes-Guerrero, K.·Tang, Y.·Das, U.·Scott, D. A.·Rangamani, P.·Roy, S.

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Abstract

Phosphorylation of -synuclein at the Serine-129 site (-syn Ser129P) is an established pathologic hallmark of synucleinopathies, and also a therapeutic target. In physiologic states, only a small fraction of total -syn is phosphorylated at this site, and consequently, almost all studies to date have focused on putative pathologic roles of this post-translational modification. We noticed that unlike native (total) -syn that is widely expressed throughout the brain, the overall pattern of -syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles. Surprisingly, preventing phosphorylation at the Ser-129 site blocked the ability of -syn to attenuate activity-dependent synaptic vesicle (SV) recycling - widely thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments -syn Ser-129P, and this phosphorylation is required for -syn binding to VAMP2 and synapsin - two functional binding-partners that are necessary for -syn function. AlphaFold2-driven modeling suggests a scenario where Ser129P induces conformational changes in the C-terminus that stabilizes this region and facilitates protein-protein interactions. Our experiments indicate that the pathology-associated Ser129P is an unexpected physiologic trigger of -syn function, which has broad implications for pathophysiology and drug-development.

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Parra-Rivas, L. A., Madhivanan, K., Wang, L., Boyer, N. P., Prakashchand, D. D., Aulston, B. D., Pizzo, D. P., Branes-Guerrero, K., Tang, Y., Das, U., Scott, D. A., Rangamani, P., Roy, S.. 2022-12-23. Serine-129 phosphorylation of α-synuclein is a trigger for physiologic protein-protein interactions and synaptic function. https://doi.org/10.1101/2022.12.22.521485

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