Kuret Jeff, Congdon Erin E, Li Guibin, Yin Haishan, Yu Xian, Zhong Qi
Department of Molecular and Cellular Biochemistry and Center for Molecular Neurobiology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210, USA.
Microsc Res Tech. 2005 Jul;67(3-4):141-55. doi: 10.1002/jemt.20187.
Alzheimer's disease is characterized in part by the aggregation of tau protein into filamentous inclusions. Because tau filaments form in brain regions associated with memory retention, and because their appearance correlates well with the degree of dementia, they have emerged as robust markers of disease progression. Yet the discovery that mutations in tau protein can lead directly to filament and tangle formation in humans, and that filament formation is linked to neurodegeneration in model biological systems, suggests that tau aggregation may also contribute directly to degeneration in affected neurons. In this context, the mechanism of tau filament formation and its modulation by mutation and posttranslational modification is of fundamental importance. Here, recent progress on the molecular mechanisms underlying tau aggregation deduced from in vivo and in vitro experimentation is reviewed and a model rationalizing the effect of posttranslational and other structural modifications on assembly kinetics and thermodynamics is presented. We hypothesize that tau aggregation can be described as a heterogeneous nucleation reaction, where exogenous effectors, tau gene mutations, or other modifications that stabilize assembly-competent conformations of tau act to trigger the fibrillization reaction. In contrast, those that modulate postnuclear equilibria can enhance fibrillization by increasing the free energy difference between polymers and unincorporated monomers, resulting in stabilization of filaments at low bulk protein concentrations.
阿尔茨海默病的部分特征是tau蛋白聚集成丝状内含物。由于tau丝在与记忆保留相关的脑区形成，且其出现与痴呆程度密切相关，因此它们已成为疾病进展的有力标志物。然而，tau蛋白突变可直接导致人类体内丝状物和缠结的形成，以及丝状物形成与模型生物系统中的神经退行性变相关这一发现表明，tau聚集也可能直接导致受影响神经元的变性。在这种情况下，tau丝形成的机制及其受突变和翻译后修饰的调控至关重要。本文综述了从体内和体外实验推导得出的tau聚集潜在分子机制的最新进展，并提出了一个解释翻译后修饰及其他结构修饰对组装动力学和热力学影响的模型。我们假设tau聚集可被描述为一种异相成核反应，其中外源性效应物、tau基因突变或其他稳定tau组装活性构象的修饰作用于引发纤维化反应。相反，那些调节核后平衡的因素可通过增加聚合物与未结合单体之间的自由能差来增强纤维化，从而在低总蛋白浓度下使丝状物稳定。
