MRC Laboratory of Molecular Biology, Cambridge, UK.
MRC Laboratory of Molecular Biology, Cambridge, UK.
Neurobiol Aging. 2018 Dec;72:98-105. doi: 10.1016/j.neurobiolaging.2018.07.022. Epub 2018 Aug 3.
The assembly of Tau into abundant β-sheet-rich filaments characterizes human tauopathies. A pathological pathway leading from monomeric to filamentous Tau is believed to be at the heart of these diseases. However, in Drosophila models of Tauopathy, neurodegeneration has been observed in the absence of abundant Tau filaments. Here we investigated the role of Tau assembly into β-sheets by expressing wild-type and Δ306-311 human Tau-383 in the retina and brain of Drosophila. We analyzed both lines for eye abnormalities, brain vacuolization, Tau phosphorylation and assembly, as well as climbing activity and survival. Flies expressing wild-type Tau-383 showed MC-1 staining, Tau hyperphosphorylation, and neurodegeneration. By contrast, flies expressing Δ306-311 Tau-383 had less MC-1 staining, reduced Tau hyperphosphorylation, and no detectable neurodegeneration. Their climbing ability and lifespan were similar to those of nontransgenic flies. Fluorescence spectroscopy after addition of Thioflavin T, a dye that interacts with β-sheets, showed no signal when Δ306-311 Tau-383 was incubated with heparin. These findings demonstrate that the assembly of Tau into β-sheets is necessary for neurodegeneration.
Tau 聚集成丰富的β-折叠纤维是人类 tau 病的特征。从单体到纤维状 Tau 的病理途径被认为是这些疾病的核心。然而，在 Tau 病的果蝇模型中，已经观察到在没有丰富的 Tau 纤维的情况下发生神经退行性变。在这里，我们通过在果蝇的视网膜和大脑中表达野生型和 Δ306-311 人 Tau-383 来研究 Tau 组装成β-片层的作用。我们分析了这两种系的眼睛异常、脑空泡化、Tau 磷酸化和组装以及攀爬活性和存活情况。表达野生型 Tau-383 的果蝇表现出 MC-1 染色、Tau 过度磷酸化和神经退行性变。相比之下，表达 Δ306-311 Tau-383 的果蝇的 MC-1 染色较少，Tau 过度磷酸化减少，且没有检测到神经退行性变。它们的攀爬能力和寿命与非转基因果蝇相似。添加与β-片层相互作用的染料 Thioflavin T 后的荧光光谱显示，当 Δ306-311 Tau-383 与肝素孵育时，没有信号。这些发现表明 Tau 组装成β-片层对于神经退行性变是必要的。
