Generation of Tau Prion Strains in Dividing Mammalian Cells

描述（由申请人提供）：tau病是一种异质性的神经退行性疾病，其特征是微管相关蛋白tau的不溶性沉积。tau蛋白错误折叠在疾病中的因果作用得到这样一个事实的支持，即与聚集倾向增加相关的多个突变导致该疾病的常显性形式。我们实验室之前的工作以及其他人的工作表明，tau蛋白可以以类似朊病毒的方式从细胞外部到细胞内部以及细胞之间进行错误折叠繁殖。这种机制模式也涉及其他疾病，包括突触核蛋白病、多谷氨酰胺扩张病和额颞叶痴呆/ALS谱系疾病。然而，与这些不同疾病相关的蛋白质是否是真正的朊病毒（由繁殖独特构象的能力定义），是一个悬而未决的问题。初步数据表明，外源性tau原纤维诱导内源性表达的tau重复结构域（RD, aa 244-372）的错误折叠，从而将其淀粉样蛋白状态稳定地传播到子细胞中，成为生化上不同的朊病毒菌株。这些构象可以从细胞中分离出来，并重新引入到原始细胞中，形成具有相同表型特征的自繁殖聚集体。来自不同tau病患者的脑匀浆诱导形成独特的tau聚集株。在初步数据的基础上，本工作提出了两个假设：1)不同的菌株与不同的牛头病有关；2)菌株的构象稳定性与其进一步聚集和诱导毒性的能力直接相关。如果成功，这项工作将为具有朊病毒病因的牛头病提供令人信服的证据，并将收集决定毒株形成、强度和毒性因素的机制见解。这项研究意义重大，因为它有助于更准确地诊断牛头病变，以及更精确地以细胞外蛋白为靶点的基于抗体的治疗，这些治疗方法作为潜在的治疗方法越来越受到关注

DESCRIPTION (provided by applicant): Tauopathies, a heterogeneous group of neurodegenerative diseases, feature insoluble deposits of the microtubule-associated protein tau. A causal role for tau misfolding in disease is supported by the fact that multiple mutations associated with an increased propensity for aggregation cause autosomally dominant forms of the disease. Previous work from our lab as well as from others' suggests that the tau protein can propagate misfolding from the outside to the inside of the cell, and between cells in a prion-like fashion. This mechanistic paradigm is also implicated in other disorders including synucleinopathies, polyglutamine expansion diseases, and frontotemporal dementia/ALS spectrum diseases. However, whether or not the proteins associated with these diverse diseases are true prions, defined by the ability to propagate unique conformations, is an unsettled matter. Preliminary data suggests that exogenous tau fibrils induce the misfolding of endogenously expressed tau repeat domain (RD, aa 244-372), which stably propagates its amyloid state to daughter cells as biochemically distinct prion strains. These conformations can be isolated from cells and re-introduced into na¿ve cells to seed self-propagating aggregates with the same phenotypic characteristics. Brain homogenates from human patients with different tauopathies induce the formation of unique tau aggregate strains. Building on preliminary data, the present work addresses two hypotheses: 1) Distinct strains are associated with distinct tauopathies; 2) There is a direct correlation between a strain's conformational stability and its ability to seed further aggregation and induce toxicity. If successful, this work will provide compelling evidence for tauopathies having a prion etiology and will gather mechanistic insight into the factors that dictate strain formation, strength, and toxicity. This research is significan because it could help lead to more accurate diagnosis of tauopathies, and to more precise antibody-based treatments that target extracellular protein, which are gaining increasing attention as potential therapies