Various metal ions promote formation of α-Synuclein fibrils with different shapes and cytotoxicities.

α-Synuclein (α-Syn) aggregates are key components of intracellular inclusion bodies characteristic of Parkinson’s disease (PD) and other synucleinopathies. Metal ions have been considered as the important etiological factors in PD since their interactions with α-Syn alter the kinetics of fibrillation. In the present study, we have systematically explored the effects of Zn 2+ , Cu 2+ , Ca 2+ , and Mg 2+ cations on α-Syn fibril formation. Specifically, we determined fibrillation kinetics, size, morphology, and secondary structure of the fibrils and their cytotoxic activity. While all cations accelerate fibrillation we observed distinct effects of the different ions. For example, Zn 2+ induced fibrillation by lower t lag and higher k app and formation of shorter fibrils, while Ca 2+ ions lead to formation of longer fibrils, evidences by dynamic light scattering and atomic force microscopy studies. Additionally, the morphology of formed fibrils was different. Circular dichroism studies revealed higher content of antiparallel β-sheets in fibrils formed in the presence of Zn 2+ . Interestingly, cell viability studies indicated nontoxicity of α-Syn fibrils formed in the presence of Zn 2+ ions, while the fibrils formed in the presence of Cu 2+ , Ca 2+ , and Mg 2+ were cytotoxic. Our results revealed that α-Syn fibrils formed in the presence of different divalent cations have distinct structural and cytotoxic features and indicate a protective role of Zn 2+ in the formation of neurotoxic α-Syn assemblies.