Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation.
Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation.
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DOI：
10.1523/jneurosci.2816-08.2008
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发表时间：
2008-11-05
期刊：
影响因子：
--
通讯作者：
Sontag E
中科院分区：
文献类型：
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作者：
Sontag JM;Nunbhakdi-Craig V;Montgomery L;Arning E;Bottiglieri T;Sontag E
叶酸稳态改变与CNS中的许多临床和病理表现相关。值得注意的是，叶酸介导的一碳代谢对于甲基转移酶依赖的细胞甲基化反应是必不可少的。蛋白磷酸酶2A（PP 2A）全酶含有调节Bα亚基，是一种主要的脑tau蛋白磷酸酶，其生物发生受甲基化控制。在这里，我们发现，在神经母细胞瘤细胞中，叶酸剥夺诱导PP 2A亮氨酸羧基甲基转移酶-1（LCMT-1）表达下调，导致新合成的去甲基化PP 2A池的进行性积累，伴随着Bα的丢失，最终导致细胞死亡。PP 2A甲基酯酶（PME-1）的过度表达进一步加剧了这些作用，但PME-1敲低不能挽救。LCMT-1或Bα的过表达足以保护细胞免受去甲基化PP 2A的积累、增加的tau磷酸化和叶酸饥饿诱导的细胞死亡。相反，敲低任一蛋白质都会加速叶酸缺乏引起的细胞毒性。值得注意的是，维持低叶酸或叶酸缺乏饮食2个月的小鼠在甲基化途径的代谢物中具有脑区域特异性改变。这些与LCMT-1、甲基化PP 2A和Bα表达下调以及易感脑区tau磷酸化增强相关。我们的研究为PP 2A甲基化和tau的调控提供了新的机制见解。他们建立了LCMT-1和含有Bα的PP 2A全酶作为叶酸在大脑中作用的关键介质。我们的研究结果表明，抵消LCMT-1和Bα的神经元损失可能对CNS的所有tau蛋白病和叶酸依赖性疾病有益。
Altered folate homeostasis is associated with many clinical and pathological manifestations in the CNS. Notably, folate-mediated one-carbon metabolism is essential for methyltransferase-dependent cellular methylation reactions. Biogenesis of protein phosphatase 2A (PP2A) holoenzyme containing the regulatory Bα subunit, a major brain tau phosphatase, is controlled by methylation. Here, we show that folate deprivation in neuroblastoma cells induces downregulation of PP2A leucine carboxyl methyltransferase-1 (LCMT-1) expression, resulting in progressive accumulation of newly-synthesized demethylated PP2A pools, concomitant loss of Bα, and ultimately cell death. These effects are further accentuated by overexpression of PP2A methylesterase (PME-1), but cannot be rescued by PME-1 knockdown. Overexpression of either LCMT-1 or Bα is sufficient to protect cells against the accumulation of demethylated PP2A, increased tau phosphorylation and cell death induced by folate starvation. Conversely, knockdown of either protein accelerates folate deficiency-evoked cell toxicity. Significantly, mice maintained for 2 months on low folate or folate-deficient diets have brain region-specific alterations in metabolites of the methylation pathway. Those are associated with downregulation of LCMT-1, methylated PP2A and Bα expression, and enhanced tau phosphorylation in susceptible brain regions. Our studies provide novel mechanistic insights into the regulation of PP2A methylation and tau. They establish LCMT-1 and Bα-containing PP2A holoenzymes as key mediators of folate’s role in the brain. Our results suggest that counteracting the neuronal loss of LCMT-1 and Bα could be beneficial for all tauopathies and folate-dependent disorders of the CNS.