A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo
A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo
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DOI：
10.1523/jneurosci.1550-17.2017
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发表时间：
2018-01-03
影响因子：
5.3
通讯作者：
Feany, Mel B.
中科院分区：
文献类型：
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作者：
Bardai, Farah H.;Wang, Liqun;Feany, Mel B.
微管结合蛋白tau与多种神经退行性疾病密切相关，包括与17号染色体（FTDP-17）相关的额颞叶痴呆和帕金森病，这是由tau突变引起的。在体外，FTDP-17突变形式的tau可以减少微管结合并增加tau的聚集，但这些突变在体内促进疾病的机制尚不清楚。在这里，我们采取生物化学和体内建模相结合的方法来定义tau蛋白在体内驱动神经毒性的功能特性。我们使用定点插入策略在果蝇中表达野生型人tau蛋白和5种FTDP-17突变形式的tau蛋白，以确保表达水平相等。然后，我们分析了转基因动物中神经变性和神经毒性的多种标志物，包括对雄性和雌性动物的分析。我们发现FTDP-17突变可增强tau蛋白的磷酸化，从而在体内环境中促进神经毒性。此外，我们证明了肌动蛋白细胞骨架的磷酸化依赖性过度稳定化是野生型tau和所有测试的FTDP-17突变体的毒性的关键磷酸化依赖性介体。最后，我们表明，重要的下游途径，包括自噬和未折叠的蛋白质反应，与神经毒性和肌动蛋白细胞骨架稳定在表达野生型人类和各种FTDP-17 tau突变体的果蝇的大脑中，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。
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. In vitro, 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 in vivo is not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo. We express wild-type human tau and five FTDP-17 mutant forms of tau in Drosophila 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 in vivo 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.