alpha-Synuclein as a Target for Metallo-Anti-Neurodegenerative Agents

The unique thermodynamic and kinetic coordination chemistry of ruthenium allows it to modulate key adverse aggregation and membrane interactions of alpha-synuclein (alpha-syn) associated with Parkinson's disease. We show that the low-toxic Ru-III complex trans-[ImH][RuCl4(Me2SO)(Im)] (NAMI-A) has dual inhibitory effects on both aggregation and membrane interactions of alpha-syn with submicromolar affinity, and disassembles pre-formed fibrils. NAMI-A abolishes the cytotoxicity of alpha-syn towards neuronal cells and mitigates neurodegeneration and motor impairments in a rat model of Parkinson's. Multinuclear NMR and MS analyses show that NAMI-A binds to residues involved in protein aggregation and membrane binding. NMR studies reveal the key steps in pro-drug activation and the effect of activated NAMI-A species on protein folding. Our findings provide a new basis for designing ruthenium complexes which could mitigate alpha-syn-induced Parkinson's pathology differently from organic agents.