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Abstract：
The microtubule associated protein, tau, is implicated in a multitude of neurodegenerative disorders that are collectively termed as tauopathies. These disorders are characterized by the presence of tau aggregates within the brain of afflicted individuals. Mutations within the MAPT gene that encodes the tau protein form the genetic backdrop for familial forms of tauopathies, such as frontotemporal dementia (FTD), but the molecular consequences of such alterations and their pathological effects are unclear. We sought to investigate the conformational properties of the aggregates of three tau mutants: A152T, P301L, and R406W, all implicated within FTD, and compare them to those of the native form (WT-Tau 2N4R). Our immunochemical analysis reveals that mutants and WT tau oligomers exhibit similar affinity for conformation-specific antibodies but have distinct morphology and secondary structure. Additionally, these oligomers possess different dye-binding properties and varying sensitivity to proteolytic processing. These results point to conformational variety among them. We then tested the ability of the mutant oligomers to cross-seed the aggregation of WT tau monomer. Using similar array of experiments, we found that cross-seeding with mutant aggregates leads to the formation of conformationally unique WT oligomers. The results discussed in this paper provide a novel perspective on the structural properties of oligomeric forms of WT tau 2N4R and its mutant, along with shedding some light on their cross-seeding behavior.
摘要：
微管相关蛋白，tau,涉及多种神经退行性疾病，统称为tau蛋白病。这些病症的特征在于在患病个体的脑内存在tau聚集体。编码tau蛋白的MAPT基因内的突变形成家族性tau蛋白病的遗传背景，如额颞叶痴呆（FTD），但是这种改变的分子后果及其病理效应尚不清楚。我们试图研究三种tau突变体的聚集体的构象特性：A152T，P301L,和R406W，都牵涉到FTD，并将它们与原生形式的(WT-Tau2N4R)进行比较。我们的免疫化学分析揭示突变体和WTtau寡聚体对构象特异性抗体表现出相似的亲和力,但具有不同的形态和二级结构。此外,这些寡聚体具有不同的染料结合性质和不同的敏感性蛋白水解加工。这些结果表明它们之间的构象多样性。然后,我们测试了突变寡聚物交叉接种WTtau单体的聚集的能力。使用类似的一系列实验，我们发现,与突变聚集体交叉接种导致构象上独特的WT寡聚体的形成。本文讨论的结果为WTtau2N4R及其突变体的寡聚形式的结构特性提供了新的视角，同时也揭示了他们的交叉播种行为。
