Structural Characterization of amyloidogenic intermediate states of Transthyretin, accessed by supercooled and pressurized conditions.
Marco C. Miotto
Max Planck Institute for Biophysical Chemistry
The misfolding of proteins into toxic conformations is proposed to be at the molecular foundation of a number of neurodegenerative disorders including Alzheimer’s Disease, Parkinson’s Disease and Senile Systemic Amyloidosis, among others. One common and defining feature of protein misfolding diseases is the formation and deposition of amyloid-like fibrils. Currently, no preventive therapy is available. The misfolding and fibrillation pathway of the proteins linked to these disorders represents then the principal target for therapeutic intervention. The detailed understanding of the phenomenon of amyloid fibrillation is clinically significant. The general purpose of this project is to access and characterize amyloidogenic intermediate states in order to understand the misfolding and fibrillation pathway. This approach will be focus on the protein Transthyretin, responsible of many amyloidosis diseases; however, the results will have high impact in all related amyloidogenic diseases. These goals will be achieved using a combination of spectroscopic techniques, including atomic resolution NMR spectroscopy, under supercooled and pressurized conditions.