| Autor: |
Nagendran Ramalingam, Shan-Xue Jin, Tim E. Moors, Luis Fonseca-Ornelas, Kazuma Shimanaka, Shi Lei, Hugh P. Cam, Aurelia Hays Watson, Lisa Brontesi, Lai Ding, Dinc Yasat Hacibaloglu, Haiyang Jiang, Se Joon Choi, Ellen Kanter, Lei Liu, Tim Bartels, Silke Nuber, David Sulzer, Eugene V. Mosharov, Weisheng V. Chen, Shaomin Li, Dennis J. Selkoe, Ulf Dettmer |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
npj Parkinson's Disease, Vol 9, Iss 1, Pp 1-15 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2373-8057 |
| DOI: |
10.1038/s41531-023-00444-w |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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