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.

在帕金森病和其他突触核蛋白病中，Serine129 磷酸化 α-突触核蛋白 （pS129） 的升高是被广泛引用的病理标志物。然而，pS129 的生理作用仍未确定。在这里，我们使用多种方法首次证明 pS129 作为神经元活动的生理调节因子发挥作用。神经元活动触发培养神经元中 pS129 的持续增加 （4 小时内 200%）。相应地，大脑 pS129 在环境富集的小鼠中升高，表现出增强的长期增强。活性依赖性 α-突触核蛋白磷酸化是 S129 特异性的，可逆的，不具有细胞毒性，并在含有突触素的突触前钮扣处积累。从机制上讲，我们的研究结果与神经元刺激通过钙/钙调神经磷酸酶途径增强 Plk2 激酶活性以抵消 PP2A 磷酸酶活性以实现膜结合的 α-突触核蛋白的有效磷酸化的模型一致。表达外源性野生型或磷酸化无能型 （S129A） α-突触核蛋白的大鼠 SNCA-/^-神经元的膜片钳制表明 pS129 微调了兴奋性和抑制性神经元电流之间的平衡。始终如一，我们的新型 S129A 敲入 （S129A^KI） 小鼠表现出海马可塑性受损。pS129 关键生理功能的发现对理解 α-突触核蛋白在神经传递中的作用具有重要意义，并为 pS129 作为突触核蛋白病生物标志物的解释增加了细微差别。