Regulation of Pathological Tau Transmission by Soluble Tau Post-Translational Modifications

积累明显的支持细胞间传递和随后病理性tau作为一种 阿尔茨海默病(AD)和其他肌萎缩侧索硬化症进展的关键机制。阻止此操作 传播过程是一种很有前途的延缓疾病进展的治疗策略。然而， 调节病理性tau传递的分子机制在很大程度上仍不清楚。以前的研究 有关tau基因传递的研究主要集中在病理性tau基因或“种子”本身。但是，它的放大 病理性tau既需要“种子”，也需要“底物”--可溶性tau。通常被忽视的是 可溶性tau对病理性tau扩增的潜在影响。我们的初步研究表明 可溶性α-突触核蛋白(a-syn)翻译后修饰(PTM)将显著影响 病理性a-syn的扩增，首次强调了PTMS对可溶性蛋白的影响 相应病理蛋白的扩增。由于在可溶性tau上发现了许多PTM，我们 假设可溶性tau PTM也会影响病理性tau扩增。事实上，我们的初步数据 证明可溶性tau乙酰化可以显著调节病理性tau的扩增。 从AD脑中制备(AD-tau)。更有趣的是，这种效应是高度病理性的tau构象 依附的。大脑皮质基底细胞变性(cbd-tau)的病理性tau表现出截然不同的反应。 与AD-tau相比，可溶tau PTMS。在这里，我们打算系统地探索可溶的tau ptm如何 会调节AD和其他tau病中病理性tau的扩增。 首先，还没有系统地鉴定和定量Tau对来自Ta病脑的可溶性tau的作用。 因此，我们建议通过以下方法系统地鉴定和定量AD和其他tau病中的可溶性tau PTM LC-MS/MS其次，我们将探索可溶性tau PTM和PTM组合如何影响 病理性tau在阿尔茨海默病和其他tau病中的放大。第三，可溶性tau ptm的作用很强。 病理性tau构象依赖。因此，我们建议评估病理性tau在 不同的疾病亚型、大脑区域和细胞类型(神经元和神经胶质细胞)会有不同的 对可溶性tau PTMS的反应。第四，研究表明，不同的细胞内环境在神经元中 神经胶质细胞会影响病理蛋白的扩增。我们建议测试不同的 细胞内环境也会改变可溶性tau蛋白的作用。最后，可溶性牛磺酸的作用 PTMS对AD-tau扩增的影响将在小鼠身上进行评估。总而言之，拟议的研究是第一个 系统探讨可溶性tau PTMS对AD和AD患者病理性tau基因扩增的影响。 其他tau病，这是一种调节tau传递的新机制。成功地演出 拟议中的研究不仅将为tau的传播提供关键的新见解，而且还将戏剧性地 促进针对阿尔茨海默病和其他牛磺酸疾病的可溶性tau PTM的新疗法的开发。

Accumulating evident support intercellular transmission and subsequent amplification of pathological tau as a key mechanism for the progression of Alzheimer’s disease (AD) and other tauopathies. Blocking this transmission process is a promising therapeutic strategy to slow down disease progression. However, the molecular mechanisms that regulate pathological tau transmission remains largely unknown. Previous studies of tau transmission have been focused on pathological tau or the ‘seed’ itself. But, the amplification of pathological tau requires both the ‘seed’ and soluble tau, the ‘substrate’. What has generally been ignored is the potential effect of soluble tau on the amplification of pathological tau. Our preliminary study demonstrated that soluble α-synuclein (a-syn) post-translational modifications (PTMs) would dramatically affect the amplification of pathological a-syn, which highlights for the first time that PTMs on soluble protein would affect amplification of the corresponding pathological protein. Since many PTMs were identified on soluble tau, we hypothesize that soluble tau PTMs will also affect pathological tau amplification. Indeed, our preliminary data demonstrated that soluble tau acetylation could dramatically modulate the amplification of pathological tau prepared from AD brains (AD-tau). More interestingly, this effect is highly pathological tau conformation dependent. Pathological tau from corticobasal degeneration brains (CBD-tau) shows very different responses to soluble tau PTMs compared with AD-tau. Here, we propose to systematically explore how soluble tau PTMs would modulate the amplification of pathological tau in AD and other tauopathies. Firstly, PTMs on soluble tau from tauopathy brains has not been systematically identified and quantified. Therefore, we propose to systematically identify and quantify soluble tau PTMs in AD and other tauopathies by LC-MS/MS. Secondly, we will explore how soluble tau PTMs and PTM combinations would affect the amplification of pathological tau in AD and other tauopathies. Thirdly, the effects of soluble tau PTMs are highly pathological tau conformation dependent. Therefore, we propose to evaluate whether pathological tau in different disease subtypes, brain regions, and cell types (neurons and glial cells), would have different responses to soluble tau PTMs. Fourthly, it has been shown that different intracellular environment in neurons and glial cells would affect the amplification of pathological proteins. We propose to test whether different intracellular environment would also change the effect of soluble tau PTMs. Finally, the effects of soluble tau PTMs on AD-tau amplification will be evaluated in mouse. In summary, the proposed study represents the first to systematically explore how soluble tau PTMs would affect the amplification of pathological tau in AD and other tauopathies, which is a novel mechanism that modulates tau transmission. Successful performance of the proposed study will not only provide critical new insights into tau transmission but also dramatically facilitate the development of novel therapies targeting soluble tau PTMs for AD and other tauopathies.