Modification of Tau by 8-Nitroguanosine 3′,5′-Cyclic Monophosphate (8-Nitro-cGMP)
Modification of Tau by 8-Nitroguanosine 3′,5′-Cyclic Monophosphate (8-Nitro-cGMP)
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8-硝基鸟苷 3′,5′-环单磷酸 (8-硝基-cGMP) 修饰 Tau
DOI：
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发表时间：
2016
影响因子：
4.8
通讯作者：
A. Takashima
中科院分区：
文献类型：
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作者：
J. Yoshitake;Y. Soeda;T. Ida;Akio Sumioka;Misato Yoshikawa;K. Matsushita;T. Akaike;A. Takashima
由细胞内过度磷酸化的tau包涵体和细胞外淀粉样β肽沉积引起的神经原纤维缠结是阿尔茨海默病的标志。Tau在外显子10的选择性剪接后的微管结合区的三个或四个重复中含有一个或两个半胱氨酸残基，并且分子间半胱氨酸二硫键的形成加速了Tau聚集。8-硝基鸟苷3′，5 ′-环磷酸（8-nitro-cGMP）是一种新型的一氧化氮（NO）第二信使，通过亲电性将cGMP共价结合到半胱氨酸残基上，这一过程被称为蛋白质S-鸟苷化。在这里，我们研究了tau蛋白的S-鸟嘌呤化及其对tau蛋白聚集的影响。8-硝基-cGMP暴露在体外和tau过表达的HEK 293 T细胞中诱导tau的S-鸟苷酸化。硫代黄素T试验中，S-鸟苷酸化tau蛋白抑制肝素诱导的tau蛋白聚集。原子力显微镜观察表明，S-鸟苷酸化的tau不能形成tau颗粒和纤维。进一步的生化分析表明，S-鸟苷酸化的tau蛋白在tau寡聚体形成的步骤中被抑制。在表达P301 L tau的Neuro 2A细胞中，8-硝基-cGMP处理显著减少了肌氨酰不溶性tau的量。tau蛋白半胱氨酸残基上的NO连接的化学修饰可以阻断tau蛋白聚集，因此，增加脑中8-硝基-cGMP水平可能成为阿尔茨海默病的潜在治疗策略。
Neurofibrillar tangles caused by intracellular hyperphosphorylated tau inclusion and extracellular amyloid β peptide deposition are hallmarks of Alzheimer's disease. Tau contains one or two cysteine residues in three or four repeats of the microtubule binding region following alternative splicing of exon 10, and formation of intermolecular cysteine disulfide bonds accelerates tau aggregation. 8-Nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP) acts as a novel second messenger of nitric oxide (NO) by covalently binding cGMP to cysteine residues by electrophilic properties, a process termed protein S-guanylation. Here we studied S-guanylation of tau and its effects on tau aggregation. 8-Nitro-cGMP exposure induced S-guanylation of tau both in vitro and in tau-overexpressed HEK293T cells. S-guanylated tau inhibited heparin-induced tau aggregation in a thioflavin T assay. Atomic force microscopy observations indicated that S-guanylated tau could not form tau granules and fibrils. Further biochemical analyses showed that S-guanylated tau was inhibited at the step of tau oligomer formation. In P301L tau-expressing Neuro2A cells, 8-nitro-cGMP treatment significantly reduced the amount of sarcosyl-insoluble tau. NO-linked chemical modification on cysteine residues of tau could block tau aggregation, and therefore, increasing 8-nitro-cGMP levels in the brain could become a potential therapeutic strategy for Alzheimer's disease.
DOI：
10.1073/pnas.84.24.9265
发表时间：
1987-12-01
影响因子：
11.1
作者：
IGNARRO, LJ;BUGA, GM;CHAUDHURI, G
通讯作者：
CHAUDHURI, G
影响因子：
4.1
作者：
Siuda J;Fujioka S;Wszolek ZK
通讯作者：
Wszolek ZK
影响因子：
3.5
作者：
Manczak, M;Anekonda, TS;Reddy, PH
通讯作者：
Reddy, PH