1. Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function.
- Author
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Parra-Rivas LA, Madhivanan K, Aulston BD, Wang L, Prakashchand DD, Boyer NP, Saia-Cereda VM, Branes-Guerrero K, Pizzo DP, Bagchi P, Sundar VS, Tang Y, Das U, Scott DA, Rangamani P, Ogawa Y, and Subhojit Roy
- Subjects
- Humans, alpha-Synuclein metabolism, Phosphorylation, Serine metabolism, Parkinson Disease metabolism, Synucleinopathies
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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