Oligomers of α-synuclein: picking the culprit in the line-up

In the present chapter, we discuss the key findings on αsyn (α-synuclein) oligomers from a biophysical point of view. Current structural methods cannot provide a high-resolution structure of αsyn oligomers due to their size, heterogeneity and tendency to aggregate. However, a low-resolution structure of a stable αsyn oligomer population is emerging based on compelling data from different research groups. αsyn oligomers are normally observed during the formation of amyloid fibrils and we discuss how they are connected to this process. Another important topic is the interaction of αsyn oligomers and membranes, and we will discuss the evidence which suggests that this interaction might be essential in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Finally, we present a remarkable example of how small molecules are able to stabilize non-amyloid oligomers and how this might be a potential strategy to inhibit the inherent toxicity of αsyn oligomers. A major challenge is to link the very complex oligomerization pathways seen in clever experiments in vitro with what actually happens in the cell. With the tremendous developments in optical microscopy in mind, we believe that it will be possible to make this link very soon.