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Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity
- Source :
- npj Parkinson's Disease, Vol 9, Iss 1, Pp 1-15 (2023)
- Publication Year :
- 2023
- Publisher :
- Nature Portfolio, 2023.
-
Abstract
- Abstract 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 −/− neurons expressing exogenous wild-type or phospho-incompetent (S129A) α-synuclein suggests that pS129 fine-tunes the balance between excitatory and inhibitory neuronal currents. Consistently, our novel S129A knock-in (S129AKI) mice exhibit impaired hippocampal plasticity. The discovery of a key physiological function for pS129 has implications for understanding the role of α-synuclein in neurotransmission and adds nuance to the interpretation of pS129 as a synucleinopathy biomarker.
- Subjects :
- Neurology. Diseases of the nervous system
RC346-429
Subjects
Details
- Language :
- English
- ISSN :
- 23738057
- Volume :
- 9
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- npj Parkinson's Disease
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.183b6fc70b54d8f9e89896f83034181
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41531-023-00444-w