Ser59 phosphorylation of 14-3-3γ modulates α-synuclein aggregation and reshapes its interactome

14-3-3 constitute a highly conserved family of proteins that participate in the regulation of essential cellular processes by establishing extensive protein-protein interactions. Consequently, perturbation of the 14-3-3s interactome can be implicated in the pathogenesis of several diseases. Phosphorylation has emerged as a key mechanism by which 14-3-3s interactome is dynamically regulated, and aberrantly phosphorylated 14-3-3s have been observed in patients with neurological disorders, among which Parkinson’s disease. Here, we investigate the role of Ser59 phosphorylation in 14-3-3γ and its impact on α-Synuclein aggregation by employing both the phosphorylated protein and the S59D phosphomimetic. Consistent with observations reported for other 14-3-3 isoforms, we found that this modification reduces the protective abilities of 14-3-3γ both in vitro and in cellular models. Importantly, this effect is also evident in cerebrospinal fluid (CSF), suggesting that phosphorylation of 14-3-3γ may directly contribute to α-Synuclein aggregation in vivo and may be relevant to disease-associated mechanisms. Using bioinformatics approaches, we further examined how Ser59 phosphorylation reshapes the global 14-3-3γ interactome, revealing novel interaction networks and pathways potentially implicated in neurodegenerative disease pathogenesis.

Authors

Institutions

Publication Details

Journal
Acta Neuropathologica Communications
Published
2026-10-09
DOI
https://doi.org/10.1186/s40478-026-02447-z
Primary Topic
14-3-3 protein interactions
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Ser59 phosphorylation of 14-3-3γ modulates α-synuclein aggregation and reshapes its interactome

Kathrin Brockmann, Giulia Rocca, Claudia Manzoni, Isabella Tessari et al.
Acta Neuropathologica Communications
14-3-3 protein interactions
article

Ser59 phosphorylation of 14-3-3γ modulates α-synuclein aggregation and reshapes its interactome

Kathrin Brockmann, Giulia Rocca, Claudia Manzoni, Isabella Tessari, Angelo Antonini, Luigi Bubacco, Stefano Capaldi, Salvatore Novello, Veronica Giusti, Lorenza Maistrello, Laura Civiero, Elisa Greggio, Giorgio Arrigoni, Marco Brucale, Roswitha Kemmner, Benjamin Röeben, Elena Giusto, Gurkirat Kaur, Isabel Wurster, Yibo Zhao
article en

Abstract

14-3-3 constitute a highly conserved family of proteins that participate in the regulation of essential cellular processes by establishing extensive protein-protein interactions. Consequently, perturbation of the 14-3-3s interactome can be implicated in the pathogenesis of several diseases. Phosphorylation has emerged as a key mechanism by which 14-3-3s interactome is dynamically regulated, and aberrantly phosphorylated 14-3-3s have been observed in patients with neurological disorders, among which Parkinson’s disease. Here, we investigate the role of Ser59 phosphorylation in 14-3-3γ and its impact on α-Synuclein aggregation by employing both the phosphorylated protein and the S59D phosphomimetic. Consistent with observations reported for other 14-3-3 isoforms, we found that this modification reduces the protective abilities of 14-3-3γ both in vitro and in cellular models. Importantly, this effect is also evident in cerebrospinal fluid (CSF), suggesting that phosphorylation of 14-3-3γ may directly contribute to α-Synuclein aggregation in vivo and may be relevant to disease-associated mechanisms. Using bioinformatics approaches, we further examined how Ser59 phosphorylation reshapes the global 14-3-3γ interactome, revealing novel interaction networks and pathways potentially implicated in neurodegenerative disease pathogenesis.

Acta Neuropathologica Communications
University of Verona (IT), University of Padua (IT), German Center for Neurodegenerative Diseases (DE), Institute of Nanostructured Materials (IT), IRCCS San Camillo Hospital (IT), Hertie Institute for Clinical Brain Research (DE), National Research Council (IT), UCL School of Pharmacy (GB), University College London (GB), University of Tübingen (DE)
Openalex Percentile: Top 23%
14-3-3 protein interactions
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.