NMR-based characterization of conformational changes occurring in the neuronal proteins alpha-Synuclein, Tau und Amyloid-beta during pathogenic oligomerization

越来越多的证据表明，蛋白质聚集体在大多数与衰老相关的神经退行性疾病的发病和进展中是重要的。在帕金森病中，这些聚集体主要由蛋白质α-突触核蛋白组成，而在阿尔茨海默病和额颞叶痴呆中，微管相关蛋白Tau形成诊断性内含物。在这里，我建议的特征Tau结合微管的结构特性，并研究Tau结合微管，结合小分子和抑制聚集的相互作用，以获得洞察功能的丧失与功能的获得的毒性机制。此外，我的目的是研究α-突触核蛋白寡聚体之间的构象差异稳定的聚集抑制剂和无添加剂，对途径寡聚体的毒性的分子机制的可溶性寡聚体，这被认为是最神经毒性的聚集体在衰老相关的神经退行性疾病的洞察。

A growing body of evidence suggests that proteinaceous aggregates are important in the onset and progression of most aging-related neurodegenerative disorders. In Parkinson’s disease these aggregates primarily consist of the protein α-synuclein, while in Alzheimer’s disease and the frontotemporal dementias the microtubule-associated protein Tau forms diagnostic inclusions. Here I propose to characterize the structural properties of Tau bound to microtubules and to study the interplay of Tau binding to microtubules, binding to small molecules and inhibition of aggregation, in order to obtain insight into toxic mechanisms of loss of function versus gain of function. In addition, I aim to study the conformational differences between α-synuclein oligomers stabilized by aggregation inhibitors and additive-free, on-pathway oligomers to obtain insight into the molecular mechanism of the toxicity of soluble oligomers, which are believed to be the most neurotoxic aggregates in aging-related neurodegenerative disorders.