Coordination of Platinum to α-Synuclein Inhibits Filamentous Aggregation in Solution.

Accumulation of filamentous aggregates of α-synuclein (AS) in Lewy bodies and neurites is characteristic of neurodegenerative diseases such as Parkinson's disease. Inhibition of AS fibrillation is helpful for understanding of AS aggregate structure and for developing chemical therapies. Herein, we report that the PtII -containing antitumor drug cisplatin suppresses filamentous aggregation of AS in solution. PtII thus contrasts strongly with reported transition-metal ions such as MnII , FeIII , and CuII , which accelerate AS aggregation. Interaction between PtII and the side chains of methionine and histidine residues was essential for inhibition of AS fibrillation. Binding of PtII to AS did not change the protein's overall random coil structure, as indicated by solution-state two-dimensional NMR and circular dichroism spectroscopy; and a solution of the AS⋅PtII complex remained free of filamentous aggregates. Our results constitute interesting new information about the biological chemistry of metal ions in Parkinson's disease and might open new lines of research into the suppression of filamentous aggregation.