Published December 23, 2022 | Version v1
Preprint Open

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

Creators

  • 1. Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA
  • 2. Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA, USA

Contributors

  • 1. Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA

Description

Phosphorylation of α-synuclein at the Serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies, and also a therapeutic target. In physiologic states, only a small fraction of α-syn is phosphorylated at this site, and most studies have focused on pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn that 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 facilitates interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug-development.

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Preprint: https://www.biorxiv.org/content/10.1101/2022.12.22.521485v1.full (URL)