Intricacies of alpha-synuclein aggregation

Abstract

Parkinson’s disease is a neurodegenerative disease characterized by the presence of abnormal deposits of aggregated proteins in the brain tissue, known as Lewy bodies. The major components of Lewy bodies are aggregated forms of a small presynaptic protein known as α-synuclein (α-syn). In this thesis we report on the intricacies of α-syn aggregation. Using an array of biophysical techniques we were able to observe the formation of the earliest α-syn oligomeric species – relatively stable dimers and tetramers – which are more easily formed than commonly assumed. Fluorescent labelling was shown to significantly affect the morphology of α-syn aggregates, which limits the applicability of this technique. From the growth kinetics of α-syn fibrillar seeds we conclude that the elongation of fibrils proceeds by a different mechanism than primary nucleation. Further, we studied the effect of solution conditions and surface effects on the growth of the α-syn aggregates. Using total internal reflection microscopy and confocal fluorescence imaging we observed the elongation of individual fibrils in real time, showing that this process proceeds by leaps and bounds.