Investigation of the Effect of Structural Modifications of Tau on Assembly State and Seeding

摘要(来自父应用程序) 尽管阿尔茨海默病(AD)总体上和tau病理生物学方面取得了重大进展，但仍有 仍然没有有效的治疗或预防阿尔茨海默病或任何其他脊椎病。为了开发这种疗法，详细地 需要了解tau的结构生物学和构效关系，包括 序列改变和翻译后修饰影响tau自组装成有毒寡聚体和 聚集体，以及这些参数如何影响tau的播种和毒性。在这里，我们提出了一个系统的、详细的 利用质谱学的最新发展研究tau病理的这些方面， 生物化学和细胞生物学方法。我们将研究初级结构变化和后处理的影响。 体外tau寡聚和聚集的翻译修饰及其体内和重组的比较 生成的牛磺酸。然后，我们将使用最近开发的一种高度 敏感的生物传感器细胞系。为了推进治疗的发展，我们还将测试组装的效果 基于tau自组装和播种的调制器。该项目的一个独特之处是结合了 PI和Co-I基团，这将使我们能够深入了解tau在多个 并回答目前悬而未决的关于管理这一关键方面的复杂过程的问题 广告。

Abstract (from parent application) Despite significant progress in Alzheimer’s disease (AD) in general and tau pathobiology in particular, there is still no effective treatment or prevention for AD or any other tauopathy. To develop such therapy, detailed knowledge of the structural biology and structure–activity relationship of tau is needed, including the way sequence alterations and post-translational modifications affect tau self-assembly into toxic oligomers and aggregates, and how these parameters impact tau seeding and toxicity. Here, we propose a systematic, detailed study of these aspects of tau pathology taking advantage of recent developments in mass-spectrometric, biochemical, and cell biology methods. We will study the effect of primary-structure alterations and post- translational modifications on tau oligomerization and aggregation in vitro and compare recombinant and in-vivo generated tau. We will then examine how all of these factors affect tau seeding using a recently developed highly sensitive biosensor cell line. To advance therapy development, we will also test the effect of assembly modulators on tau self-assembly and seeding. A unique aspect of the project is the combination of expertise of the PI and Co-I groups, which will allow obtaining insight into the structure–activity relationship of tau on multiple levels and answering currently pending questions about the complex processes governing this crucial aspect of AD.