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

积累明显的证据支持病理性tau蛋白的细胞间传递和随后的扩增， 阿尔茨海默病（AD）和其他tau蛋白病进展的关键机制。阻断这种 传播过程是减缓疾病进展的有前景的治疗策略。但 调节病理性tau蛋白传递的分子机制仍然是未知的。以前的研究 研究人员一直关注病理性tau蛋白或“种子”本身。但是， 病理性tau需要“种子”和可溶性tau，即“底物”。通常被忽视的是， 可溶性tau蛋白对病理性tau蛋白扩增的潜在影响。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，这首次强调了可溶性蛋白上的PTM会影响 相应病理蛋白的扩增。由于在可溶性tau上鉴定了许多PTM，我们 假设可溶性tau PTM也将影响病理性tau扩增。事实上，我们的初步数据 表明可溶性tau蛋白乙酰化可以显著调节病理性tau蛋白的扩增， 从AD脑（AD-tau）制备。更有趣的是，这种影响是高度病理性的tau构象 依赖。来自皮质基底节变性脑（CBD-tau）的病理性tau蛋白显示出非常不同的反应 与AD-tau相比，可溶性tau PTM。在这里，我们建议系统地探索可溶性tau蛋白翻译后修饰是如何 将调节AD和其他tau蛋白病中病理性tau蛋白的扩增。 首先，尚未系统地鉴定和定量来自tau蛋白病脑的可溶性tau蛋白上的PTM。 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蛋白病中的可溶性tau蛋白PTM： 其次，我们将探索可溶性tau PTM和PTM组合将如何影响tau蛋白的表达。 AD和其他tau蛋白病中病理性tau蛋白的扩增。第三，可溶性tau PTM的作用是高度的。 病理性tau构象依赖性。因此，我们建议评估是否病理性tau蛋白在 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 PTM的反应。第四，已经表明，神经元中的不同细胞内环境 神经胶质细胞会影响病理蛋白的扩增。我们建议测试是否不同 细胞内环境也会改变可溶性tau PTM的作用。最后，可溶性tau蛋白 将在小鼠中评价对AD-tau扩增的PTM。总之，拟议的研究是第一个 系统地探索可溶性tau蛋白PTM如何影响AD中病理性tau蛋白的扩增， 其他tau蛋白病，这是一种调节tau蛋白传递的新机制。顺利履行 拟议的研究不仅将为tau蛋白的传播提供重要的新见解， 有助于开发针对AD和其他tau蛋白病的靶向可溶性tau PTM的新疗法。

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.