Acute administration of L-DOPA induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain.
Acute administration of L-DOPA induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain.
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DOI：
10.1523/jneurosci.0125-12.2012
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发表时间：
2012-07-04
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影响因子：
--
通讯作者：
Sontag E
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文献类型：
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作者：
Bottiglieri T;Arning E;Wasek B;Nunbhakdi-Craig V;Sontag JM;Sontag E
叶酸缺乏和低甲基化与许多与年龄相关的神经退行性疾病有关，包括痴呆和帕金森病（PD）。PD患者的左旋多巴（L-dopa）治疗已被证明会导致血浆总同型半胱氨酸（tHcy）升高，以及甲基供体s -腺苷蛋氨酸（SAM）的细胞浓度降低，并增加去甲基化产物s -腺苷同型半胱氨酸（SAH）。细胞SAM/SAH比例的调节可以影响甲基转移酶的活性，包括亮氨酸羧基甲基转移酶（LCMT1），该酶特异性地甲基化丝氨酸/苏氨酸蛋白磷酸酶2A (PP2A)，这是一种主要的Tau磷酸酶。我们在人类SH-SY5Y细胞和多巴胺能神经元以及野生型小鼠中显示，左旋多巴导致SAM/SAH比例降低，这与PP2A的低甲基化和阿尔茨海默病样PHF-1磷酸化表位上Tau （p-Tau）的磷酸化增加有关。在叶酸缺乏的细胞中，左旋多巴对PP2A和p-Tau的影响加剧。在叶酸缺乏小鼠模型中，左旋多巴导致大脑各区域SAM明显减少，SAH增加，PP2A甲基化平行下调，Tau磷酸化增加。左旋多巴也增加了肝脏中去甲基化PP2A的数量。这些发现揭示了一种涉及甲基化依赖途径的新机制，其中左旋多巴诱导PP2A低甲基化并增加Tau磷酸化，这可能对神经元细胞有害。
Folate deficiency and hypomethylation have been implicated in a number of age-related neurodegenerative disorders including dementia and Parkinson’s disease (PD). Levodopa (L-dopa) therapy in PD patients has been shown to cause an increase in plasma total homocysteine (tHcy) as well as depleting cellular concentrations of the methyl donor, S-adenosylmethionine (SAM), and increasing the demethylated product S-adenosylhomocysteine (SAH). Modulation of the cellular SAM/SAH ratio can influence activity of methyltransferase enzymes including leucine carboxyl methyltransferase (LCMT1), that specifically methylates Ser/Thr protein phosphatase 2A (PP2A), a major Tau phosphatase. Here we show in human SH-SY5Y cells and dopaminergic neurons, and in wild type mice that L-dopa results in a reduced SAM/SAH ratio that is associated with hypomethylation of PP2A and increased phosphorylation of Tau (p-Tau) at the Alzheimer disease-like PHF-1 phosphoepitope. The effect of L-dopa on PP2A and p-Tau was exacerbated in cells exposed to folate deficiency. In the folate deficient mouse model, L-dopa resulted in a marked depletion of SAM and increase in SAH in various brain regions with parallel down regulation of PP2A methylation and increased Tau phosphorylation. L-dopa also enhanced demethylated PP2A amounts in the liver. These findings reveal a novel mechanism involving methylation-dependent pathways in which L-dopa induces PP2A hypomethylation and increases Tau phosphorylation, which may be potentially detrimental to neuronal cells.