AI Article Synopsis
- Ruthenium's unique chemical properties can reduce harmful aggregation and membrane interactions of α-synuclein linked to Parkinson's disease.
- The low-toxicity ruthenium complex NAMI-A inhibits α-synuclein aggregation and disassembles existing fibrils while preventing toxicity to neuronal cells in Parkinson's models.
- Research shows that NAMI-A targets specific protein residues and suggests potential for developing new ruthenium-based therapies distinct from traditional treatments.
Article Abstract
The unique thermodynamic and kinetic coordination chemistry of ruthenium allows it to modulate key adverse aggregation and membrane interactions of α-synuclein (α-syn) associated with Parkinson's disease. We show that the low-toxic Ru complex trans-[ImH][RuCl (Me SO)(Im)] (NAMI-A) has dual inhibitory effects on both aggregation and membrane interactions of α-syn with submicromolar affinity, and disassembles pre-formed fibrils. NAMI-A abolishes the cytotoxicity of α-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 α-syn-induced Parkinson's pathology differently from organic agents.
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| http://dx.doi.org/10.1002/anie.202215360 | DOI Listing |
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