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Serine-129 phosphorylation of α-synuclein is a trigger for physiologic protein-protein interactions and synaptic function
Open accessPreprint — published as 10.1016/j.neuron.2023.11.020
Abstract
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 total α-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) α-syn that is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles. Surprisingly, preventing phosphorylation at the Ser-129 site blocked the ability of α-syn to attenuate activity-dependent synaptic vesicle (SV) recycling – widely thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments α-syn Ser-129P, and this phosphorylation is required for α-syn binding to VAMP2 and synapsin – two functional binding-partners that are necessary for α-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 α-syn function, which has broad implications for pathophysiology and drug-development.
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Metadata
- Authors
- 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.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Roy, Subhojit
- ORCID
- Venue
- Neuron
- Publisher
- openRxiv
- Published
- 2022-12-23
- Volume
- 111
- Issue
- 24
- Pages
- 4006-4023.e10
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC10766085
- OpenAlex
- W4389992959
- Cited by
- 127
- References
- 1
- Citations by year
- 2026: 38 · 2025: 47 · 2024: 39 · 2023: 3
- FWCI
- 21.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Neuron (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (ASAP-020495)
- Parkinson's Disease Foundation (PF-LAUNCH-1046253)
- American Parkinson Disease Association
- Emory University (UL1 TR002378)
- Johns Hopkins University
- Parkinson's Foundation (PF-LAUNCH-1046253)
- Georgia Clinical and Translational Science Alliance (UL1-TR002378)
- Aligning Science Across Parkinson’s (P30NS047101, ASAP-020495)
- Farmer Family Foundation
- Nanyang Technological University
- National Institutes of Health (1s10od023527-01, UL1TR002378)
- School of Medicine, Emory University (UL1-TR002378)
- University of California, San Diego (SCR_022039, P30 NS047101, RRID: SCR_022039, S10OD023527)
- National Institute of Neurological Disorders and Stroke (S10OD023527, R01NS111978, P30NS047101)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, serine 129 phosphorylation, synucleinopathies, synaptic function, protein-protein interaction, neuronal activity, conformational change, synapses, post-translational modification, drug development
- MeSH terms
- Synucleinopathies, Humans, Parkinson Disease, Phosphorylation, Serine, alpha-Synuclein
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