Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity.
Journal
NPJ Parkinson's disease
ISSN: 2373-8057
Titre abrégé: NPJ Parkinsons Dis
Pays: United States
ID NLM: 101675390
Informations de publication
Date de publication:
16 Jan 2023
16 Jan 2023
Historique:
received:
12
07
2022
accepted:
22
12
2022
entrez:
16
1
2023
pubmed:
17
1
2023
medline:
17
1
2023
Statut:
epublish
Résumé
In Parkinson's disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA
Identifiants
pubmed: 36646701
doi: 10.1038/s41531-023-00444-w
pii: 10.1038/s41531-023-00444-w
pmc: PMC9842642
doi:
Types de publication
Journal Article
Langues
eng
Pagination
4Subventions
Organisme : NINDS NIH HHS
ID : R01 NS099328
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS122880
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109510
Pays : United States
Informations de copyright
© 2023. The Author(s).
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