Structure of dopamine induced α-synuclein oligomers

Inclusions of aggregated α-synuclein (α-syn) in dopaminergic neurons are a characteristic histological marker of Parkinson’s disease (PD). In vitro, α-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 α-syn oligomers formed in the presence of DA. Our SAXS data show that the trimers formed by the action of DA on α-syn consist of overlapping worm-like monomers, with no end-to-end associations. This lack of structure contrasts with the well-established, extensive β-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 α-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 β-sheet structure found in other pre-fibrillar forms of α-syn. © 2010, Springer.

Keywords

Dopamine, EPR spectrometers, Small angle scattering, Diseases, Agglomeration, Proteins

Citation

Rekas, A., Knott, R. B., Sokolova, A., Barnham, K. J., Perez, K. A., Masters, C. L., Drew, S. C., Cappai, R., Curtain, C. C., & Pham, C. L. L. (2010). Structure of dopamine induced α-synuclein oligomers. European Biophysics Journal, 39(10), 1407-1419. doi:10.1007/s00249-010-0595-x