Science and Technology Production
FENS Forum 2024 - Federation of European Neuroscience Societies - DAD9, a novel agonist concept that breaks the lethal partnership between a-Synuclein and dopamine
Congress
Authorship:
Chehín Rosana ; Teran, María del Milagro ; Budeguer Isa, Valentina ; Cruz, Hernán ; Tomas-Grau, RH ; GUAYÁN, MARÍA LAURA ; Pernicone, Agustín O. ; Manzano, Verónica E. ; Delprato, CB ; De Mendoza, D ; Varela, Oscar ; Ploper, DiegoDate:
2024Publishing House and Editing Place:
Federation of European Neuroscience SocietiesSummary *
Aims: Recently, we introduced DAD9, a chemically-modified tetracycline (TC) conjugated to DA, creating a dopaminergic agonist with neuroprotective effects for Parkinson's Disease (PD). Our aim is to deepen the understanding of the molecular mechanisms underlying DAD9's neuroprotection.Methods: Characterization of α-Synuclein (α-Syn) oligomeric species was performed using ThT fluorescence, SDSPAGE, DLS, and microscopy. Cell culture assays measured viability, cytotoxicity, and intracellular seeding in transgenic cell models. In vivo experiments were conducted in transgenic C. elegans.Results: The TC residue within DAD9 shielded the DA residue from oxidation, preventing the formation of dopaminochrome or neuromelanin, toxic cyclic derivatives. Furthermore, α-Syn species formed in the presence of DAD9, generated a distinct type of aggregated species, which were ThS (+), SDS-sensitive, and showed reduced toxicity in vitro and in vivo. Moreover, unlike doxycycline, DAD9 did not delay growth in C. elegans, suggesting a lack of off-target effect on eukaryotic translation, adding on to the previously reported safety profile.Conclusion: These findings suggest the DA moiety in the novel concept drug DAD9 lacked the ability to oxidize into toxic species, redirected α-Syn oligomers toward distinct off-pathway species, and the TC portion did not affect eukaryotic ribosomes. In conclusion, the chemical design in DAD9 reduced off-target effects of each of its parent compounds, positioning this novel multitarget neuroprotective dopaminergic agonist as a promising candidate for future preclinical and clinical studies. Information provided by the agent in SIGEVAKey Words
Parkinson's DiseaseOligomersTetracycline derivativesAlpha-synucleinDAD9Neuroprotection