Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, and.
Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045.
J Neurosci. 2018 Jan 3;38(1):108-119. doi: 10.1523/JNEUROSCI.1550-17.2017. Epub 2017 Nov 14.
The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. , FTDP-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease is not clear. Here we take a combined biochemical and modeling approach to define functional properties of tau driving neurotoxicity We express wild-type human tau and five FTDP-17 mutant forms of tau in using a site-directed insertion strategy to ensure equivalent levels of expression. We then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic animals, including analysis of both males and females. We find that FTDP-17 mutations act to enhance phosphorylation of tau and thus promote neurotoxicity in an setting. Further, we demonstrate that phosphorylation-dependent excess stabilization of the actin cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the FTDP-17 mutants tested. Finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis. The microtubule protein tau aggregates and forms insoluble inclusion bodies known as neurofibrillary tangles in the brain tissue of patients with a variety of neurodegenerative disorders, including Alzheimer's disease. The tau protein is thus widely felt to play a key role in promoting neurodegeneration. However, precisely how tau becomes toxic is unclear. Here we capitalize on an "experiment of nature" in which rare missense mutations in tau cause familial neurodegeneration and neurofibrillary tangle formation. By comparing the biochemical activities of different tau mutations with their toxicity in a well controlled model system, we find that all mutations tested increase phosphorylation of tau and trigger a cascade of neurotoxicity critically impinging on the integrity of the actin cytoskeleton.
微管结合蛋白 tau 强烈参与多种神经退行性疾病，包括额颞叶痴呆和与染色体 17 相关的帕金森病（FTDP-17），该疾病是由 tau 突变引起的。FTDP-17 突变型 tau 可降低微管结合并增加 tau 的聚集，但这些突变促进疾病的机制尚不清楚。在这里，我们采用组合的生化和建模方法来定义驱动神经毒性的 tau 的功能特性。我们使用定点插入策略在 中表达野生型人类 tau 和五种 FTDP-17 突变型 tau，以确保表达水平相等。然后，我们分析了转基因动物中的多种神经退行性和神经毒性标志物，包括雄性和雌性动物的分析。我们发现，FTDP-17 突变会增强 tau 的磷酸化，从而在 中促进神经毒性。此外，我们证明，磷酸化依赖性的肌动蛋白细胞骨架过度稳定是野生型 tau 和所有测试的 FTDP-17 突变体毒性的关键磷酸化依赖性介质。最后，我们表明，重要的下游途径，包括自噬和未折叠蛋白反应，与表达野生型人类和各种 FTDP-17 tau 突变体的苍蝇脑中的神经毒性和肌动蛋白细胞骨架稳定密切相关，支持野生型 tau 和 FTDP-17 突变体 tau 在疾病发病机制中的神经毒性的保守机制。微管蛋白 tau 在包括阿尔茨海默病在内的多种神经退行性疾病患者的脑组织中聚集并形成不溶性包含体，称为神经原纤维缠结。因此，tau 蛋白被广泛认为在促进神经退行性变中发挥关键作用。然而，tau 如何变得有毒尚不清楚。在这里，我们利用 tau 中的罕见错义突变导致家族性神经退行性变和神经原纤维缠结形成的“自然实验”。通过比较不同 tau 突变的生化活性与其在高度受控的 模型系统中的毒性，我们发现所有测试的突变都增加了 tau 的磷酸化，并引发了一系列神经毒性，严重影响了肌动蛋白细胞骨架的完整性。
