Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
PLoS One. 2020 Apr 28;15(4):e0232019. doi: 10.1371/journal.pone.0232019. eCollection 2020.
Parkinson's disease (PD) is a common neurodegenerative disorder which is mostly sporadic but familial-linked PD (FPD) cases have also been found. The first reported gene mutation that linked to PD is α-synuclein (α-syn). Studies have shown that mutations, increased expression or abnormal processing of α-syn can contribute to PD, but it is believed that multiple mechanisms are involved. One of the contributing factors is post-translational modification (PTM), such as phosphorylation of α-syn at serine 129 by G-protein-coupled receptor kinases (GRKs) and casein kinase 2α (CK2α). Another known important contributing factor to PD pathogenesis is oxidative and nitrosative stress. In this study, we found that GRK6 and CK2α can be S-nitrosylated by nitric oxide (NO) both in vitro and in vivo. S-nitrosylation of GRK6 and CK2α enhanced their kinase activity towards the phosphorylation of α-syn at S129. In an A53T α-syn transgenic mouse model of PD, we found that increased GRK6 and CK2α S-nitrosylation were observed in an age dependent manner and it was associated with an increased level of pSer129 α-syn. Treatment of A53T α-syn transgenic mice with Nω-Nitro-L-arginine (L-NNA) significantly reduced the S-nitrosylation of GRK6 and CK2α in the brain. Finally, deletion of neuronal nitric oxide synthase (nNOS) in A53T α-syn transgenic mice reduced the levels of pSer129 α-syn and α-syn in an age dependent manner. Our results provide a novel mechanism of how NO through S-nitrosylation of GRK6 and CK2α can enhance the phosphorylation of pSer129 α-syn in an animal model of PD.
帕金森病（PD）是一种常见的神经退行性疾病，大多数为散发性，但也发现了家族性相关 PD（FPD）病例。与 PD 相关的第一个被报道的基因突变是α-突触核蛋白（α-syn）。研究表明，α-syn 的突变、表达增加或异常加工可导致 PD，但据信涉及多种机制。促成因素之一是翻译后修饰（PTM），例如 G 蛋白偶联受体激酶（GRK）和酪蛋白激酶 2α（CK2α）将α-syn 丝氨酸 129 磷酸化。导致 PD 发病机制的另一个已知重要促成因素是氧化和硝化应激。在这项研究中，我们发现 GRK6 和 CK2α 可以在体外和体内被一氧化氮（NO）S-亚硝化。GRK6 和 CK2α 的 S-亚硝化增强了它们对α-syn 丝氨酸 129 磷酸化的激酶活性。在 PD 的 A53T α-syn 转基因小鼠模型中，我们发现 GRK6 和 CK2α 的 S-亚硝化随年龄增长而增加，与 pSer129 α-syn 水平增加有关。用 Nω-硝基-L-精氨酸（L-NNA）治疗 A53T α-syn 转基因小鼠可显著降低大脑中 GRK6 和 CK2α 的 S-亚硝化。最后，在 A53T α-syn 转基因小鼠中敲除神经元型一氧化氮合酶（nNOS）可降低 pSer129 α-syn 和 α-syn 的水平，呈年龄依赖性。我们的结果提供了一种新的机制，即 NO 通过 GRK6 和 CK2α 的 S-亚硝化如何增强 PD 动物模型中 pSer129 α-syn 的磷酸化。
