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

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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.