Roles of tau protein in health and disease.
Roles of tau protein in health and disease.
复制标题
DOI：
10.1007/s00401-017-1707-9
复制
发表时间：
2017-05
影响因子：
12.7
通讯作者：
Hanger DP
中科院分区：
文献类型：
--
作者：
Guo T;Noble W;Hanger DP
Tau被公认为神经元中的微管相关蛋白。然而，在病理条件下，tau异常组装成不溶性聚集体伴随着一系列神经退行性疾病中的突触功能障碍和神经细胞死亡，统称为tau蛋白病。最近的进展，在我们的理解的多种功能和不同的位置tau内外的神经元已经揭示了新的见解，其重要性在不同范围的分子途径，包括细胞信号传导，突触可塑性，和调节基因组的稳定性。本综述介绍了tau蛋白的生理和病理生理特性，以及这些特性与其在神经元中的分布和功能的关系。我们强调了tau的翻译后修饰，这在定义和调节tau定位及其在健康和疾病中的作用方面至关重要。我们还讨论了tau蛋白的其他病理相关变化，包括突变和聚集，以及这些方面如何影响tau蛋白在患病大脑中传播的倾向，并可能导致神经元丢失。最后，我们描述了可能由tau蛋白功能障碍驱动的级联病理事件，包括受损的轴突运输，突触和线粒体功能的改变，未折叠蛋白反应的激活和有缺陷的蛋白降解。重要的是要充分了解归因于tau的神经元功能的范围，因为这将提供有关其参与疾病发展和发病机制的重要信息。这样的知识将使得能够确定哪些关键分子途径应该被开发用于治疗tau蛋白病的潜在治疗剂靶向。
Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability. The present review describes the physiological and pathophysiological properties of tau and how these relate to its distribution and functions in neurons. We highlight the post-translational modifications of tau, which are pivotal in defining and modulating tau localisation and its roles in health and disease. We include discussion of other pathologically relevant changes in tau, including mutation and aggregation, and how these aspects impinge on the propensity of tau to propagate, and potentially drive neuronal loss, in diseased brain. Finally, we describe the cascade of pathological events that may be driven by tau dysfunction, including impaired axonal transport, alterations in synapse and mitochondrial function, activation of the unfolded protein response and defective protein degradation. It is important to fully understand the range of neuronal functions attributed to tau, since this will provide vital information on its involvement in the development and pathogenesis of disease. Such knowledge will enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies.