The structure of dopamine induced alpha-synuclein oligomers

Inclusions of aggregated I?-synuclein (I?-syn) in dopaminergic neurons are a characteristic histological marker of Parkinson s disease (PD). In vitro, I?-syn in the presence of dopamine (DA) at physiological pH forms SDS-resistant non-amyloidogenic oligomers. We used a combination of biophysical techniques, including sedimentation velocity analysis, small angle X-ray scattering (SAXS) and circular dichroism spectroscopy to study the characteristics of I?-syn oligomers formed in the presence of DA. Our SAXS data show that the trimers formed by the action of DA on I?-syn consist of overlapping worm-like monomers, with no end-to-end associations. This lack of structure contrasts with the well-established, extensive I?-sheet structure of the amyloid fibril form of the protein and its pre-fibrillar oligomers. We propose on the basis of these and earlier data that oxidation of the four methionine residues at the C- and N-terminal ends of I?-syn molecules prevents their end-to-end association and stabilises oligomers formed by cross linking with DA-quinone/DA-melanin, which are formed as a result of the redox process, thus inhibiting formation of the I?-sheet structure found in other pre-fibrillar forms of I?-syn