Tau protein accumulation is a common denominator of major dementias, but this process is inhomogeneous, even when triggered by the same germline mutation. We considered stochastic misfolding of human tau conformers followed by templated conversion of native monomers as an underlying mechanism and derived sensitive conformational assays to test this concept. Assessments of brains from aged TgTauP301L transgenic mice revealed a prodromal state and three distinct signatures for misfolded tau. Frontotemporal lobar degeneration (FTLD)-MAPT-P301L patients with different clinical phenotypes also displayed three signatures, two resembling those found in TgTauP301L mice. As physicochemical and cell bioassays confirmed diverse tau strains in the mouse and human brain series, we conclude that evolution of diverse tau conformers is intrinsic to the pathogenesis of this uni-allelic form of tauopathy. In turn, effective therapeutic interventions in FTLD will need to address evolving repertoires of misfolded tau species rather than singular, static molecular targets.

中文翻译：

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不同的、不断进化的构象群体在由相同的 MAPT-P301L 突变引起的额颞叶变性中驱动不同的表型。


Tau 蛋白积累是严重痴呆症的一个共同点，但这个过程是不均匀的，即使是由相同的种系突变触发的。我们考虑人类 tau 构象异构体的随机错误折叠，然后对天然单体进行模板化转换作为潜在机制，并衍生出敏感的构象测定来测试这一概念。对老年 TgTauP301L 转基因小鼠大脑的评估揭示了前驱状态和错误折叠 tau 蛋白的三个不同特征。具有不同临床表型的额颞叶变性 (FTLD)-MAPT-P301L 患者也表现出三种特征，其中两种与 TgTauP301L 小鼠中发现的相似。由于物理化学和细胞生物测定证实了小鼠和人类大脑系列中存在多种 tau 菌株，因此我们得出结论，多种 tau 构象异构体的进化是这种单等位基因形式 tau 病的发病机制所固有的。反过来，FTLD 的有效治疗干预措施需要解决错误折叠 tau 蛋白物种的不断演变，而不是单一的静态分子靶点。