Role of sulfhydration on the functions of the microtubule associated protein, Tau

项目总结 硫化氢是一种具有神经保护作用的气体信号分子。会产生硫化氢 通过反向硫化途径从半胱氨酸和/或同型半胱氨酸内源。硫化氢的生产是 在老年痴呆症(AD)和硫化氢捐赠者中减少，阿尔茨海默病(AD)是老年人痴呆的最常见原因 已经被报道具有有益的效果。然而，这种下降的机制基础仍然没有 已被阐明。硫化氢通过翻译后修饰调节几个生理过程 作为硫水化作用，其中反应性半胱氨酸残基的-SH基团转化为过硫化物或-SSH 组。我们和其他人之前进行的研究表明，在衰老期间，这是患糖尿病的最大风险因素 发展为阿尔茨海默病时，大脑中的硫水化作用减少。我们进行的初步研究表明，Tau、 微管相关蛋白是AD中神经原纤维缠结的一种成分，与胱硫氨酸γ裂解酶结合 (CSE)，硫化氢的生物合成酶之一，并激活它。 在这项研究中，我们建议表征三种生物合成酶对硫化氢，CSE， 体外细胞培养中的半胱硫氨酸β合成酶和3-硫代丙酮酸硫转移酶 在小鼠的大脑中也是如此。我们还试图阐明H_2S对Tau活性的影响。在AIM 1、研究CSE、CBS和3-MST与野生型Tau及其异构体的结合。在目标2中，我们将评估 研究了牛磺酸的硫水化状态，并将半胱氨酸残基映射到硫水化的牛磺酸上。破译 H_2S/Tau途径的信号功能不仅将识别tau的基本生理功能，而且还将识别 精确定位AD治疗干预的结节，这些结节也与其他tauopathy相关。

PROJECT SUMMARY Hydrogen sulfide (H2S) is a gaseous signaling molecule which has neuroprotective effects. H2S is generated endogenously from cysteine and/or homocysteine via the reverse transsulfuration pathway. H2S production is diminished in Alzheimer's disease (AD), the most common cause of dementia in the elderly, and H2S donors have been reported to confer beneficial effects. However, the mechanistic basis for this decrease has still not been elucidated. H2S regulates several physiological processes via a posttranslational modification designated as sulfhydration, wherein the -SH groups of reactive cysteine residues are converted to persulfide or -SSH groups. Prior studies conducted by us and others show that during aging, which is the biggest risk factor for developing AD, sulfhydration is decreased in the brain. Preliminary studies conducted by us show that Tau, the microtubule associated protein, and a component of neurofibrillary tangles in AD, binds cystathionine γ-lyase (CSE), one of the biosynthetic enzymes for H2S and activates it. In this study we propose to characterize the interaction of the three biosynthetic enzymes for H2S, CSE, cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), both in vitro in cell culture as well as in vivo in the mouse brain. We also seek to elucidate the effects of H2S on the activity of Tau. In Aim 1, we will study the binding of CSE, CBS and 3-MST to wild type Tau and its isoforms. In Aim 2, we will evaluate the sulfhydration status of Tau and map the cysteine residues on tau which are sulfhydrated. Deciphering the signaling functions of the H2S/Tau pathway will not only identify basic physiological functions of tau, but also pinpoint nodes for therapeutic intervention in AD, which are also relevant for other tauopathies.