The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease
The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease
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DOI：
10.1073/pnas.0711053105
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发表时间：
2008-01-15
影响因子：
11.1
通讯作者：
Muzyczka, Nicholas
中科院分区：
文献类型：
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作者：
Gorbatyuk, Oleg S.;Li, Shoudong;Muzyczka, Nicholas
研究表明，帕金森病(PD)患者脑组织路易体中沉积的α-突触核蛋白(α-syn)在Ser-129处被广泛磷酸化。我们使用重组腺相关病毒(RAAV)在大鼠黑质纹状体束过表达人野生型(Wt)α-syn和两个人α-syn突变体，并将Ser-129定点替换为丙氨酸(S129A)或天冬氨酸(S129D)，以观察Ser-129磷酸化状态对多巴胺能神经元病理的影响。在大鼠一侧黑质致密部(SNC)注射rAAV2/5载体，另一侧作为非转导对照。注射侧表达的人wt或突变体α-syn的水平大约是内源性大鼠α-syn的四倍。注射S129A后4wk，黑质多巴胺能神经元明显减少，纹状体多巴胺(DA)和酪氨酸羟化酶(TH)水平明显降低。注射wt的动物黑质DA病理发生较慢，但到26 wk时wtα-syn组与突变的S129A组在8 wk时失去了与突变的S129A组相当的黑质TH神经元。与之形成鲜明对比的是，我们没有观察到S129D处理的动物的任何病理变化。因此，S129的非磷酸化形式加剧了α-SYN诱导的黑质病理，而Ser-129的磷酸化则消除了α-SYN诱导的黑质纹状体变性。这表明帕金森病可能有新的治疗靶点。
Studies have shown that alpha-synuclein (alpha-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) alpha-syn and two human alpha-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 substantial 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 alpha-syn expressed on the injected side was about four times the endogenous rat alpha-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 alpha-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 nonphosphorylated form of S129 exacerbates alpha-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates alpha-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.