Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation
Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation
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DOI：
10.1073/pnas.2017225118
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发表时间：
2021-01-26
影响因子：
11.1
通讯作者：
Paul, Bindu D.
中科院分区：
文献类型：
--
作者：
Giovinazzo, Daniel;Bursac, Biljana;Paul, Bindu D.
阿尔茨海默病(AD)是老年人痴呆症和神经退行性变的最常见原因，其特征是记忆力、执行和运动功能恶化。阿尔茨海默病的神经病理特征包括神经纤维缠结(NFT5)、成对的螺旋细丝和淀粉样斑块。微管相关蛋白Tau是NFT5的主要组成部分，它的突变导致其在AD中过度磷酸化。我们已经证明，在衰老过程中，由气体分子硫化氢(H_2S)发出的信号是失调的。H_2S通过一种被称为硫水化/过硫化的翻译后修饰来传递信号，该修饰参与多种细胞过程。在这里，我们发现胱硫醚伽马裂解酶(CSE)是一种生物合成H_2S的酶，它与野生型Tau结合，从而增强了其催化活性。相比之下，CSE未能结合Tau P301L，Tau P301L是一种存在于AD 3xTg-AD小鼠模型中的突变。我们进一步表明，CSE在3xTg-AD小鼠和人类AD脑中都是耗尽的，而H_2S通过硫酸水合Tau的激酶，糖原合成酶激酶3β(GSK3β)来防止Tau的过度磷酸化。最后，我们证明了在AD中硫水化作用减少，而给3xTg-AD小鼠服用硫化氢供体GYY4137钠(NaGYY)可以改善AD中的运动和认知障碍。
Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFT5), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFT5, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine gamma-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3 beta (GSK3 beta). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.