Lyu Chen, Da Vela Stefano, Al-Hilaly Youssra, Marshall Karen E, Thorogate Richard, Svergun Dmitri, Serpell Louise C, Pastore Annalisa, Hanger Diane P
Department of Basic and Clinical Neuroscience, King's College London, London, United Kingdom.
European Molecular Biology Laboratory, Hamburg Site, Hamburg, Germany.
Front Mol Biosci. 2021 Oct 28;8:779240. doi: 10.3389/fmolb.2021.779240. eCollection 2021.
Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Tau35 may have structural properties distinct from those of other tau species that could account for its pathological role in disease. To address this hypothesis, we performed a structural characterization of monomeric and aggregated Tau35 and compared the results to those of two longer isoforms, 2N3R and 2N4R tau. We used small angle X-ray scattering to show that Tau35, 2N3R and 2N4R tau all behave as disordered monomeric species but Tau35 exhibits higher rigidity. In the presence of the poly-anion heparin, Tau35 increases thioflavin T fluorescence significantly faster and to a greater extent than full-length tau, demonstrating a higher propensity to aggregate. By using atomic force microscopy, circular dichroism, transmission electron microscopy and X-ray fiber diffraction, we provide evidence that Tau35 aggregation is mechanistically and morphologically similar to previously reported tau fibrils but they are more densely packed. These data increase our understanding of the aggregation inducing properties of clinically relevant tau fragments and their potentially damaging role in the pathogenesis of human tauopathies.
Tau35是在人类大脑中tau蛋白病的一个亚组中发现的tau蛋白截短形式。小鼠中Tau35的表达重现了人类疾病的关键特征，包括tau蛋白磷酸化的逐渐增加，以及认知和运动功能障碍。聚集的tau蛋白的出现表明，Tau35可能具有与其他tau蛋白物种不同的结构特性，这可以解释其在疾病中的病理作用。为了验证这一假设，我们对单体和聚集态的Tau35进行了结构表征，并将结果与两种较长的异构体2N3R和2N4R tau进行了比较。我们使用小角X射线散射表明，Tau35、2N3R和2N4R tau均表现为无序的单体物种，但Tau35表现出更高的刚性。在多阴离子肝素存在的情况下，Tau35比全长tau更快且更显著地增加硫黄素T荧光，表明其聚集倾向更高。通过使用原子力显微镜、圆二色性、透射电子显微镜和X射线纤维衍射，我们提供证据表明，Tau35聚集在机制和形态上与先前报道的tau原纤维相似，但它们堆积得更紧密。这些数据加深了我们对临床相关tau片段的聚集诱导特性及其在人类tau蛋白病发病机制中潜在破坏作用的理解。
