2100 København Ø
In this project, we aim to understand how co-structural dynamics of αsn and membrane constituents define and/or alter the biological function by using multidisciplinary approaches, particularly by integration of several structural methods for in vitro characterization and cell biology techniques for functional characterization. Structural and functional aspects of αsn will be studied on with regard to membrane interactions and with a goal of achieving an understanding of how the protein can be therapeutically targeted. Nuclear magnetic resonance Spectroscopy (NMR) and small angle X-ray and neutron scattering (SAXS and SANS) will be employed monitoring αsn:lipid interactions and the structures of co-aggregates. Lipid carriers (vesicles, nano-disks and selected cellular systems) will be produced to perform a structural characterization of αsn:lipid synergistic interaction. Additionally, different conformational equilibria points from the fibrillation pathway of αsn (native monomer, pre-fibrillar oligomeric species, amyloid fibrils) will be investigated to determine which equilibria mostly cause the cytotoxic effect since there has been brought long debates for many years to make a decision on it. The ultimate goal of the project is to enable rational design of therapeutics targeting the fuzzy interactions between αsn and lipid bilayer environment.