D-114 | DAD9, a novel dopaminergic agonist with neuroprotective properties, avoids dopamine oxidation and inhibits aggregation of α-Synuclein into toxic species

Neurochemistry and Neuropharmacology
Author: María Terán | Email: maria0191@hotmail.com

María del Milagro Teran^1°, Hernán Cruz^2°, Valentina Budeguer Isa^1°,  Diego Ploper^1°, Rosana Chehín^1°

^1° Instituto de Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), San Miguel de Tucumán, Argentina
^2° Universidad Nacional de Tucumán (UNT), San Miguel de Tucumán, Argentina

The innovative compound DAD9, a chemically modified non-antibiotic tetracycline (TC) conjugated to dopamine (DA), was synthetized to create a dopaminergic agonist with neuroprotective properties for Parkinson’s disease (PD). This study aimed to investigate the mechanisms underlying the neuroprotective effects of DAD9 using a model of α-Synuclein (α-Syn) oligomers stabilized with DA. The characterization of α-Syn oligomeric species was performed through ThT fluorescence, SDS-PAGE, dynamic light scattering (DLS), and viability assays in neuronal cell lines.
Our results indicate that the DA moiety in DAD9 was protected from oxidation, effectively preventing the formation of neuromelanin, a toxic and insoluble polymer. Notably, the α-Syn species formed in the presence of DAD9 produced a distinct type of aggregated species, which differed if size, lacked cross-β structure, and exhibited reduced toxicity in vitro.
These findings demonstrate that the DA moiety in DAD9 was incapable of suffering oxidation into toxic species. In addition, DAD9, either though its DA or TC moiety, redirected the formation of α-Syn oligomers towards non-toxic off-pathway species, distinct from those stabilized by DA. In conclusion, this research elucidates a novel mechanism of action for DAD9 as a multitarget neuroprotective dopaminergic agonist, offering promising implications for PD treatments.