S-nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy
S-nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy
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DOI：
10.1038/s41398-019-0388-7
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发表时间：
2019-01-29
影响因子：
6.8
通讯作者：
Tannenbaum, Steven R.
中科院分区：
文献类型：
--
作者：
Amal, Haitham;Gong, Guanyu;Tannenbaum, Steven R.
编码tau蛋白的MAPT基因的突变与几种神经退行性疾病有关，包括额颞叶痴呆（FTD），癫痫痴呆和其他类型的痴呆。FTD P301 S小鼠模型中Mapt基因的错义突变导致3月龄时突触功能受损和小胶质细胞增生，这是疾病的最早表现。在这里，我们研究了2个月大的转基因P301 S小鼠的S-亚硝基蛋白质组的变化，以检测对应于疾病进展早期阶段的分子事件。在P301 S和野生型（WT）同窝对照小鼠的两个脑区（皮质和海马）中鉴定了S-亚硝基化（SNO）蛋白。我们发现在这两个地区的群体之间的S-亚硝基蛋白质组的重大变化。使用GO和途径分析，几种途径会聚以显示钙调节和非经典Wnt信号传导受到影响。在CA 1和内嗅皮层区域发现3-硝基酪氨酸的显著增加，这表明氧化应激和一氧化氮形成的升高。有证据表明P301 S小鼠皮质中的非经典Wnt/Ca++（NC-WCa）信号传导增加;包括磷酸化CaMKII和E3泛素蛋白连接酶RNF 213（RNF 213）的S-亚硝基化增加，导致活化T细胞核因子1（NFAT-1）和FILAMIN-A水平增加，这进一步放大了NC-WCa并促成了病理学。这些发现暗示了tau蛋白病中NC-WCa途径的激活，并提供了S-亚硝基化对NC-WCa激活的贡献的新见解，并为治疗tau蛋白病提供了新的潜在药物靶点。
Mutations in the MAPT gene, which encodes the tau protein, are associated with several neurodegenerative diseases, including frontotemporal dementia (FTD), dementia with epilepsy, and other types of dementia. The missense mutation in the Mapt gene in the P301S mouse model of FTD results in impaired synaptic function and microgliosis at three months of age, which are the earliest manifestations of disease. Here, we examined changes in the S-nitrosoproteome in 2-month-old transgenic P301S mice in order to detect molecular events corresponding to early stages of disease progression. S-nitrosylated (SNO) proteins were identified in two brain regions, cortex and hippocampus, in P301S and Wild Type (WT) littermate control mice. We found major changes in the S-nitrosoproteome between the groups in both regions. Several pathways converged to show that calcium regulation and non-canonical Wnt signaling are affected using GO and pathway analysis. Significant increase in 3-nitrotyrosine was found in the CA1 and entorhinal cortex regions, which indicates an elevation of oxidative stress and nitric oxide formation. There was evidence of increased Non-Canonical Wnt/Ca++ (NC-WCa) signaling in the cortex of the P301S mice; including increases in phosphorylated CaMKII, and S-nitrosylation of E3 ubiquitin-protein ligase RNF213 (RNF213) leading to increased levels of nuclear factor of activated T-cells 1 (NFAT-1) and FILAMIN-A, which further amplify the NC-WCa and contribute to the pathology. These findings implicate activation of the NC-WCa pathway in tauopathy and provide novel insights into the contribution of S-nitrosylation to NC-WCa activation, and offer new potential drug targets for treatment of tauopathies.