Common structural features of toxic intermediates from α-synuclein and GroES fibrillogenesis detected using cryogenic coherent X-ray diffraction imaging.

The aggregation and deposition of alpha-synuclein (alpha Syn) in neuronal cells is correlated to pathogenesis of Parkinson's disease. Although the mechanism of alpha Syn aggregation and fibril formation has been studied extensively, the structural hallmarks that are directly responsible for toxicity toward cells are still under debate. Here, we have compared the structural characteristics of the toxic intermediate molecular species of alpha Syn and similar toxic species of another protein, GroES, using coherent X-ray diffraction analysis. Using coherent X-ray free electron laser pulses of SACLA, we analysed alpha Syn and GroES fibril intermediate species and characterized various aggregate structures. Unlike previous studies where an annular oligomeric form of alpha Syn was identified, particle reconstruction from scattering traces suggested that the specific forms of the toxic particles were varied, with the sizes of the particles falling within a specific range. We did however discover a common structural feature in both alpha Syn and GroES samples; the edges of the detected particles were nearly parallel and produced a characteristic diffraction pattern in the diffraction experiments. The presence of parallel-edged particles in toxic intermediates of alpha Syn and GroES fibrillogenesis pointed towards a plausible common molecular interface that leads to the formation of mature fibrils.