Copper binding to the physiological form of the alpha-synuclein protein

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The human alpha-synuclein (AS) protein is associated with the pathogenesis of Parkinsons disease (PD) and other neurodegenerative disorders. In PD, AS is the primary component of Lewy-bodies, a proteinaceous deposit in the substantia nigra (a part of the midbrain). The causes and mechanisms of the self-aggregation of AS protein are unknown. Copper ions, which are found to be harmful in Alzheimers disease, accelerate aggregation of the non-physiological, non-acetylated form of AS in aqueous solution, where the protein is naturally unfolded. Both Cu(I) and Cu(II) ions may play a role in the neuron derangement associated with PD. While structural insights on the non-acetylated, non-physiological form are available, those on the physiologically relevant acetylated form (AcAS) are lacking. However, spectral properties of the Cu(I)-AS form are very similar to the ones of Cu(I)-AcAS. Thus, the conclusions of structural studies regarding Cu(I)-AS remain basically valid for Cu(I)-AcAS. This contrasts with Cu(II) binding to AcAS, which is completely different from that to AS. Here we plan to predict Cu(II)-AcAS structural determinants by molecular simulation. Comparison between calculated NMR, EXAFS and CD spectra and the experimental ones, measured by our collaborator Claudio Fernandez for this research, will establish the reliability of our predictions. Our study may provide the first valuable new insights on how metals, in particular copper, modulate AS fibril formation process. This could be crucial for the development of new drug-design approaches.