Interaction Between α-Synuclein and Metal Ions, Still Looking for a Role in the Pathogenesis of Parkinson’s Disease

The most recent literature on the interaction between α-synuclein in its several aggregation states and metal ions is discussed. This analysis shows two major types of interactions. Binding sites are present in the C-terminal region, and similar, low affinity (in the millimolar range) is exhibited toward many different metal ions, including copper and iron. A more complex scenario emerges for these latter metal ions, which are also able to coordinate with high affinity (in the micromolar range) to the N-terminal region of α-synuclein. Moreover, these redox-active metal ions may induce chemical modifications on the protein in vitro and in the reducing intracellular environment, and these modifications might be relevant for the aggregation properties of α-synuclein. Finally, an attempt is made to contextualize the interaction between α-synuclein and these metal ions in the framework of the elusive and multifactorial pathogenesis of Parkinson’s disease.