Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Adv Exp Med Biol. 2019;1184:359-372. doi: 10.1007/978-981-32-9358-8_26.
This chapter discusses the relationship between tau, RNA binding proteins and stress granules, which exhibit an intimate bidirectional relationship affecting the functions of both tau and the translational stress response. We describe how tau becomes hyperphosphorylated and oligomerized as part of an endogenous mechanism to promote the translational stress response through interaction with RNA binding proteins. Prior studies demonstrate that dysfunction of RNA binding proteins biology is sufficient to cause neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Emerging evidence indicates that tau-mediated neurodegeneration also occurs through a mechanism that is mediated by RNA binding proteins and the translational stress response. Discovery of the role of RNA metabolism in tauopathy opens a wide variety of novel therapeutic approaches. Multiple studies have already shown that approaches reducing the levels of selected RNA binding proteins or inhibiting the translational stress response can intervene in the pathophysiology of motoneuron diseases. Emerging studies show that reducing the levels of selected RNA binding proteins or inhibiting the translational stress response also reduces neurodegeneration in models of tauopathy and Aβ mediated degeneration. The combined impact of these studies indicate that RNA binding proteins and RNA metabolism represent a valuable new frontier for the investigation and treatment tauopathies.
这一章讨论了 tau 与 RNA 结合蛋白和应激颗粒之间的关系，它们之间存在着密切的双向关系，影响着 tau 和翻译应激反应的功能。我们描述了 tau 如何作为一种内源性机制的一部分被过度磷酸化和寡聚化，从而通过与 RNA 结合蛋白相互作用来促进翻译应激反应。先前的研究表明，RNA 结合蛋白生物学功能障碍足以导致神经退行性疾病，如肌萎缩侧索硬化症和额颞叶痴呆症。新出现的证据表明，tau 介导的神经退行性变也通过 RNA 结合蛋白和翻译应激反应介导的机制发生。RNA 代谢在 tau 病中的作用的发现为多种新的治疗方法开辟了道路。多项研究已经表明，降低特定 RNA 结合蛋白的水平或抑制翻译应激反应的方法可以干预运动神经元疾病的病理生理学。新出现的研究表明，降低特定 RNA 结合蛋白的水平或抑制翻译应激反应也可以减少 tau 病和 Aβ 介导的变性模型中的神经退行性变。这些研究的综合影响表明，RNA 结合蛋白和 RNA 代谢代表了 tau 病研究和治疗的一个有价值的新前沿。
