Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity

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

doi:10.1038/s41531-023-00444-w

Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity

NPJ Parkinsons Dis. 2023 Jan 16;9(1):4. doi: 10.1038/s41531-023-00444-w.

Authors

Nagendran Ramalingam¹, Shan-Xue Jin^#², Tim E Moors^#², Luis Fonseca-Ornelas², Kazuma Shimanaka², Shi Lei³, Hugh P Cam³, Aurelia Hays Watson⁴, Lisa Brontesi², Lai Ding², Dinc Yasat Hacibaloglu², Haiyang Jiang², Se Joon Choi⁵, Ellen Kanter⁵, Lei Liu², Tim Bartels⁴, Silke Nuber², David Sulzer^{5

6

7}, Eugene V Mosharov^{5

6}, Weisheng V Chen³, Shaomin Li², Dennis J Selkoe², Ulf Dettmer⁸

Affiliations

¹ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. nramalingam@bwh.harvard.edu.
² Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
³ Leveragen, Inc., 17 Briden Street, Worcester, MA, 01605, USA.
⁴ UK Dementia Research Institute, University College London, London, UK.
⁵ Division of Molecular Therapeutics, New York State Psychiatric Institute, Research Foundation for Mental Hygiene, New York, NY, 10032, USA.
⁶ Departments of Neurology and Psychiatry, Columbia University Medical Center, New York, NY, 10032, USA.
⁷ Department of Molecular Therapeutics and Pharmacology, Columbia University Medical Center, New York, NY, 10032, USA.
⁸ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. udettmer@bwh.harvard.edu.

^# Contributed equally.

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 (S129A^KI) 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.

Abstract

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