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Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function.
Parra-Rivas, Leonardo A; Madhivanan, Kayalvizhi; Aulston, Brent D; Wang, Lina; Prakashchand, Dube Dheeraj; Boyer, Nicholas P; Saia-Cereda, Veronica M; Branes-Guerrero, Kristen; Pizzo, Donald P; Bagchi, Pritha; Sundar, V S; Tang, Yong; Das, Utpal; Scott, David A; Rangamani, Padmini; Ogawa, Yuki.
Affiliation
  • Parra-Rivas LA; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
  • Madhivanan K; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Aulston BD; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Wang L; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Prakashchand DD; Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA, USA.
  • Boyer NP; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Saia-Cereda VM; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Branes-Guerrero K; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Pizzo DP; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Bagchi P; Emory Integrated Proteomics Core, Emory University, Atlanta, GA, USA.
  • Sundar VS; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Tang Y; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Das U; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Scott DA; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA.
  • Rangamani P; Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA, USA.
  • Ogawa Y; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
  • Subhojit Roy; Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA
Neuron ; 111(24): 4006-4023.e10, 2023 Dec 20.
Article in En | MEDLINE | ID: mdl-38128479
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Parkinson Disease / Synucleinopathies Limits: Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2023 Document type: Article Affiliation country: United States
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Parkinson Disease / Synucleinopathies Limits: Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2023 Document type: Article Affiliation country: United States