共核细胞病
磷酸化
神经科学
细胞生物学
丝氨酸
功能(生物学)
生物
蛋白质磷酸化
突触可塑性
α-突触核蛋白
化学
生物化学
帕金森病
受体
蛋白激酶A
医学
内科学
疾病
作者
Leonardo A Parra‐Rivas,Kayalvizhi Madhivanan,Brent Aulston,Lina Wang,Dube Dheeraj Prakashchand,Nicholas P. Boyer,Verônica M. Saia‐Cereda,Kristen Branes‐Guerrero,Donald Pizzo,Pritha Bagchi,V. S. Sundar,Yong Tang,Utpal Das,David A. Scott,Padmini Rangamani,Yuki Ogawa,Subhojit Roy
出处
期刊:Neuron
[Elsevier]
日期:2023-12-01
卷期号:111 (24): 4006-4023.e10
被引量:29
标识
DOI:10.1016/j.neuron.2023.11.020
摘要
Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn—thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development.
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