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FENS 2024 Federation of european neuroscience societies - DAD9, a novel agonist concept that breaks the lethal partnership between α-synuclein and dopamine
Congress
Authorship:
Chehín, R ; Teran, María del Milagro ; Budeguer Isa, Valentina ; Cruz, Hernán ; TOMAS GRAU, RODRIGO HERNÁN ; Guayan, ML ; Pernicore, A ; Manzano, V ; DelPrato, CB ; De Mendoza, D ; Varela O ; Ploper, DDate:
2024Publishing House and Editing Place:
FENSSummary *
Aims: Recently, we introduced DAD9, a chemically-modified tetracycline (TC) conjugated to DA, creating adopaminergic agonist with neuroprotective effects for Parkinson´s Disease (PD). Our aim is to deepen theunderstanding 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 intransgenic 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 ofdopaminochrome or neuromelanin, toxic cyclic derivatives. Furthermore, α-Syn species formed in the presence ofDAD9, generated a distinct type of aggregated species, which were ThS (+), SDS-sensitive, and showed reducedtoxicity in vitro and in vivo. Moreover, unlike doxycycline, DAD9 did not delay growth in C. elegans, suggesting alack 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 oxidizeinto toxic species, redirected α-Syn oligomers toward distinct off-pathway species, and the TC portion did notaffect eukaryotic ribosomes. In conclusion, the chemical design in DAD9 reduced off-target effects of each of itsparent compounds, positioning this novel multitarget neuroprotective dopaminergic agonist as a promisingcandidate for future preclinical and clinical studies. Information provided by the agent in SIGEVAKey Words
AgonistDopamineDAD9a-synuclein