Glaucoma is a neurodegenerative disorder that leads to the slow degeneration of retinal ganglion cells, and results in damage to the optic nerve and concomitant vision loss. As in other disorders affecting the viability of central nervous system neurons, neurons affected by glaucoma do not have the ability to regenerate after injury. Recent studies indicate a critical role for optic nerve head astrocytes (ONHAs) in this process of retinal ganglion cell degeneration. Cleavage of tau, a microtubule stabilizing protein and constituent of neurofibrillary tangles (NFT), plays a major part in the mechanisms that lead to toxicity in CNS neurons and astrocytes. Here, we tested the hypothesis that estrogen, a pleiotropic neuro- and cytoprotectant with high efficacy in the CNS, prevents tau cleavage, and hence, protects ONHAs against cell damage caused by oxidative stress. Our results indicate that estrogen prevents caspase-3 mediated tau cleavage, and thereby decreases the levels of the resulting form of proteolytically cleaved tau protein, which leads to a decrease in NFT formation, which requires proteolytically cleaved tau protein. Overall, our data propose that by stopping the reduction of estrogen levels involved with aging the sensitivity of the optic nerve to glaucomatous damage might be reduced. Furthermore, our data suggest that therapeutic use of estrogen may be beneficial in slowing or preventing the onset or severity of neurodegenerative diseases such as glaucoma and potentially also other degenerative diseases of the CNS through direct control of posttranslational modifications of tau protein.

中文翻译：

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雌激素通过防止 Caspase-3 激活、Tau Ser422 去磷酸化以及 Tau 蛋白聚集体的形成，保护视神经头星形胶质细胞免受氧化应激。


青光眼是一种神经退行性疾病，会导致视网膜神经节细胞缓慢变性，并导致视神经损伤并伴随视力丧失。与影响中枢神经系统神经元活力的其他疾病一样，受青光眼影响的神经元在损伤后没有再生能力。最近的研究表明视神经乳头星形胶质细胞 (ONHA) 在视网膜神经节细胞变性过程中发挥着关键作用。 tau 蛋白是一种微管稳定蛋白，也是神经原纤维缠结 (NFT) 的组成部分，它的裂解在导致中枢神经系统神经元和星形胶质细胞毒性的机制中发挥着重要作用。在这里，我们测试了这样的假设：雌激素是一种对中枢神经系统具有高效作用的多效性神经和细胞保护剂，可防止 tau 裂解，从而保护 ONHA 免受氧化应激引起的细胞损伤。我们的结果表明，雌激素可阻止 caspase-3 介导的 tau 裂解，从而降低所得形式的蛋白水解 tau 蛋白的水平，从而导致 NFT 形成减少，而 NFT 需要蛋白水解裂解的 tau 蛋白。总的来说，我们的数据表明，通过停止与衰老相关的雌激素水平的降低，视神经对青光眼损伤的敏感性可能会降低。此外，我们的数据表明，通过直接控制 tau 蛋白的翻译后修饰，雌激素的治疗​​用途可能有益于减缓或预防青光眼等神经退行性疾病的发作或严重程度，也可能有益于其他中枢神经系统退行性疾病。