NMR-based characterization of conformational changes occurring in the neuronal proteins alpha-Synuclein, Tau und Amyloid-beta during pathogenic oligomerization
Final Report Abstract
The goal of my research is to push NMR spectroscopy into new research areas and to provide insights at the molecular level into the factors that are responsible for the neurotoxicity of the proteins alpha-synuclein, Tau and amyloid-beta peptide during the course of Parkinson’s and Alzheimer’s disease. In addition, we strive to obtain structurefunction relationships for integral membrane proteins, such as the human voltage dependent anion channel (VDAC). In recent years we made significant progress along these lines. We are at the forefront of the structural and dynamic study of intrinsically disordered proteins in neurodegeneration, in particular the Tau protein. By going from structural biology to animal models of Parkinson disease we have provided strong evidence that the acutely toxic species are oligomeric species of α-synuclein. In addition, we revealed the presence of extensive slow time-scale dynamics in the VDAC1 barrel that laid the basis for new models of voltage gating in VDAC1 relying on deformation of the barrel shape.
Publications
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(2010). Functional dynamics in the voltage-dependent anion channel. Proc Natl Acad Sci USA 107, 22546-51
Villinger, S. et al.
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(2011). The dynamic structure of filamentous tau. Angew Chem Int Ed Engl 50, 11520-4
Bibow, S., Mukrasch, M.D., Chinnathambi, S., Biernat, J., Griesinger, C., Mandelkow, E. and Zweckstetter, M.
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(2013). Inhibition of tau filament formation by conformational modulation. J Am Chem Soc 135, 2853-62
Akoury, E., Gajda, M., Pickhardt, M., Biernat, J., Soraya, P., Griesinger, C., Mandelkow, E. and Zweckstetter, M.
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(2013). Mechanistic basis of phenothiazine-driven inhibition of Tau aggregation. Angew Chem Int Ed Engl 52, 3511-5
Akoury, E., Pickhardt, M., Gajda, M., Biernat, J., Mandelkow, E. and Zweckstetter, M.
