Soluble oligomers are potent toxins in many neurodegenerative diseases, but little is known about the structure of soluble oligomers and their structure-toxicity relationship. Here we prepared onpathway oligomers of the 140-residue protein R-synuclein, a key player in Parkinson's disease, at concentrations an order of magnitude higher than previously possible. The oligomers form ion channels with well-defined conductance states in a variety of membranes, and their -structure differs from that of amyloid fibrils of R-synuclein.

The relation of a-synuclein (aS) aggregation to Parkinson's disease has long been recognized, but the pathogenic species and its molecular properties have yet to be identified. To obtain insight into the properties of aS in an aggregation-prone state, we studied the structural properties of aS at acidic pH using NMR spectroscopy and computation. NMR demonstrated that aS remains natively unfolded at lower pH, but secondary structure propensities were changed in proximity to acidic residues. The ensemble of conformations of aS at acidic pH is characterized by a rigidification and compaction of the Asp and Glu-rich C-terminal region, an increased probability for proximity between the NAC-region and the C-terminal region and a lower probability for interactions between the N-and C-terminal regions.