Translational Structural Biology in Dementia

Prof. Dr. Markus Zweckstetter

Areas of investigation/research focus

The three-dimensional structure of biomolecules determines their physiological function. Changes in three-dimensional structure and formation of aberrant protein conformations results in disease. Aberrant protein folding in liquid-liquid phase separated states, soluble oligomers and amyloid fibrils is intimately linked to the progression of neurodegenerative diseases and insoluble deposits of the proteins Tau and alpha-synuclein are pathological hallmarks of several neurodegenerative disorders including Alzheimer’s and Parkinson’s disease. The goal of our research is therefore to provide mechanistic insights into the misfolding and pathogenic aggregation of proteins in Alzheimer’s and Parkinson’s disease. To this end, we combine biophysical analysis, in particular high-resolution NMR spectroscopy, with biochemical experiments and translate the experiments through collaborations into cellular/animal models of AD/PD. Our work aims to identify novel targets/conformations/mechanisms for small molecule intervention and thus novel strategies for diagnosis and therapy of neurodegenerative diseases.

For many years now we used NMR spectroscopy to understand Tau structure as a way to understand Tau function and its mechanisms of action. In collaboration with the Mandelkow group, we obtained detailed insight into the structural polymorphism of Tau, phosphorylation at different sites, influence of aggregation enhancers on the conformational ensemble of Tau, and provided insight into the fuzzy coat of insoluble Tau deposits at unprecedented detail. Ground-breaking findings were gained with respect to the interaction of Tau with microtubules and the molecular chaperone Hsp90. In addition, we determined the three-dimensional structure of a misfolded cytotoxic monomer of the amyloidogenic protein transthyretin, studied the influence of the clinically-important T119M mutation and characterized the interaction of transthyretin with Hsp90. The combined date indicated that human Hsp90 uses a unique mechanism for the recognition of toxic misfolded proteins. Another breakthrough was the finding that the microtubule-binding repeats of Tau undergo liquid-liquid phase separation in solution. This work established a mechanism in which liquid droplets formed by the positively-charged microtubule-binding domain of Tau undergo coacervation with negatively-charged molecules to promote amyloid formation in Alzheimer’s disease. A further highlight of our work was the determination of the 3D structure of the translocator protein TSPO in complex with a diagnostic ligand as well as insights into the allosteric regulation of TSPO structure by cholesterol.

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