A calorimetric study of α-synuclein fibril formation & peptide induced vesicle leakage

Sammanfattning: The small protein α-synuclein is strongly associated with Parkinson’s disease. This protein is found in inclusion bodies, named lewy bodies inside neurons of people suffering from the disease. α-synuclein is very abundant in the human brain, and its normal function is still elusive and unclear. The factors that trigger the accumulation and fibrillation of this protein into pathogenic inclusion bodies is of great interest in the quest of finding a cure for the disease. In this study the isothermal fibrillation of this protein from monomeric form (found in the brain of healthy people) into aggregated structures (found in people with the disease) was investigated using calorimetry. This yielded insights about the underlying thermodynamics that govern the onset and progression of the disease. This work shows that the process of fibrillation is endothermic (needs energy to proceed) under the investigated conditions and that calorimetry is a method that may be employed in the study of this protein. Attempts were made to investigate whether this protein had an effect on proton permeability across the membrane of small unilamellar vesicles, with a pH gradient between the interior and exterior of the vesicles. In doing so groundwork was laid for developing a vesicle leakage assay using the lytic peptide melittin and studying leakage through isothermal titration calorimetry.