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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease
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The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease

机译：人α-突触核蛋白中Ser-129的磷酸化状态决定帕金森病大鼠模型中的神经变性

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Studies have shown that α-synuclein (α-syn) deposited in Lewy bodies in brain tissue from patients with Parkinson disease (PD) is extensively phosphorylated at Ser-129. We used recombinant Adeno-associated virus (rAAV) to overexpress human wild-type (wt) α-syn and two human α-syn mutants with site-directed replacement of Ser-129 to alanine (S129A) or to aspartate (S129D) in the nigrostriatal tract of the rat to investigate the effect of Ser-129 phosphorylation state on dopaminergic neuron pathology. Rats were injected with rAAV2/5 vectors in the substantia nigra pars compacta (SNc) on one side of the brain; the other side remained as a nontransduced control. The level of human wt or mutant α-syn expressed on the injected side was about four times the endogenous rat α-syn. There was a significant reduction of dopaminergic neurons in the SNc and dopamine (DA) and tyrosine hydroxylase (TH) levels in the striatum of all S129A-treated rats as early as 4 wk postinjection. Nigral DA pathology occurred more slowly in the wt-injected animals, but by 26 wk the wt a-syn group lost nigral TH neurons equivalent to the mutated S129A group at 8 wk. In stark contrast, we did not observe any pathological changes in S129D-treated animals. Therefore, the nonphosphory-lated form of S129 exacerbates α-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates α-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.
机译：研究表明，帕金森病（PD）患者脑组织中路易体中沉积的α-突触核蛋白（α-syn）在Ser-129处广泛磷酸化。我们使用重组腺相关病毒（rAAV）过量表达人类野生型（wt）α-syn和两个人类α-syn突变体，将Ser-129定点替换为丙氨酸（S129A）或天冬氨酸（S129D）。大鼠黑质纹状体以研究Ser-129磷酸化状态对多巴胺能神经元病理的影响。大鼠在大脑一侧的黑质致密部（SNc）中注射了rAAV2 / 5载体。另一侧仍作为非转导对照。在注射侧表达的人类野生型或突变型α-syn的水平约为内源大鼠α-syn的四倍。早在注射后4周，所有S129A治疗的大鼠的SNc中的多巴胺能神经元和纹状体中的多巴胺（DA）和酪氨酸羟化酶（TH）水平均显着降低。在注射wt的动物中，黑色DA的病理发生较慢，但是到了26周，wt a-syn组在8周时失去了与突变的S129A组相当的黑色TH神经元。与之形成鲜明对比的是，我们在S129D处理的动物中未观察到任何病理变化。因此，S129的非磷酸化形式加剧了α-syn诱导的黑质病变，而Ser-129磷酸化消除了α-syn诱导的黑质纹状体变性。这提示了帕金森氏病可能的新治疗靶标。

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