Broad-Spectrum Suppression and Disassembly of α-Synuclein Variant Aggregates Mediated by a Ruthenium Metallodrug via Conserved Metal-Coordination

Abstract

Inhibiting α-synuclein (α-Syn) aggregation is a promising therapeutic strategy for Parkinson's disease (PD); however, its structural disorder and heterogeneity of aggregates across familial variants pose significant challenges. Here, we demonstrate that NAMI-A, a ruthenium-based compound effectively inhibits aggregation of wildtype and pathogenic familial α-Syn variants. Biophysical and biochemical analyses revealed that NAMI-A binds α-Syn via coordination to conserved regions, preventing the structural transition to β-sheet and inhibiting aggregation. Notably, NAMI-A dismantles preformed aggregates of diverse structures from various pathogenic variants. Cellular assays confirmed that NAMI-A significantly reduces α-Syn-induced cytotoxicity in neuronal cells by attenuating ROS generation. This work establishes that metallo-agents can act as broad-spectrum therapeutic agents to overcome mutation-dependent limitations for PD treatment.