Structural and cellular features that control the aggregation of a-synuclein into amyloid

Many amyloid precursors are intrinsically disordered initially, yet fold to highly organised cross-b structures during amyloid formation. How this conformational transition occurs structurally is not clear, with the initiating steps in aggregation being difficult to study because of the dynamics and heterogeneity of the species involved. It is also clear that regions flanking the key amyloid-forming regions can have dramatic effects on the progress of assembly. The neuronal protein α-synuclein (αSyn), linked to pathology in Parkinson’s disease and several other synucleopathies, is one such protein. In this talk I will describe our recent exploration into the early stages of aggregation of αSyn in which we have focussed on the role of the N-terminal region of the protein in modulating and controlling it aggregation behaviour. Using in silico methods to predict potential regions of interest, creating deletion variants, and analysing the rates of aggregation of these variants and their conformational properties using NMR methods, we have identified new regions in the N-terminal region of the protein that have a major impact on its amyloid behaviour and its function in remodelling lipids. The results highlight the complexity in energy landscape of this IDP in which functional constraints have resulted in the evolution of a protein with enhanced amyloid potential.