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Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function.
- Source :
-
Neuron . Dec2023, Vol. 111 Issue 24, p4006-4006. 1p. - Publication Year :
- 2023
-
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. • Native α-syn serine-129 phosphorylation is seen in discrete brain regions • Preventing α-syn serine-129 phosphorylation blocks activity-dependent α-syn functions • Neuronal activity augments α-syn serine-129 phosphorylation in cells and in vivo • α-syn serine-129 phosphorylation triggers protein-protein interactions at synapses Phosphorylation of α-synuclein at the serine-129 site is an established pathologic hallmark of Parkinson's disease and related "synucleinopathies," but new findings from Parra-Rivas et al. suggest a physiologic role for this post-translational modification in triggering α-synuclein function by facilitating protein-protein interactions at synapses. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08966273
- Volume :
- 111
- Issue :
- 24
- Database :
- Academic Search Index
- Journal :
- Neuron
- Publication Type :
- Academic Journal
- Accession number :
- 174294762
- Full Text :
- https://doi.org/10.1016/j.neuron.2023.11.020