V-108 | Unraveling the Toxicity of α-Synuclein oligomers: A Novel In Vivo Model

Neurochemistry and Neuropharmacology
Author: Ana Valentina Budeguer Isa | Email: vbudeguer@gmail.com

Valentina Budeguer Isa^1°2°, María del Milagro Terán^1°2°,Hernán Cruz^1°3°, Diego Ploper^1°2°, Rosana Chehín^1°2°

^1° IMMCA (Instituto de Investigación en Medicina Molecular y Celular Aplicada)
^2° CONICET
^3° UNT
^4° SIPROSA

The presynaptic protein α-synuclein (α-Syn) is crucial in Parkinson’s disease (PD) and other synucleinopathies, forming β-sheet-rich amyloid fibrils and toxic oligomeric species (α-Synoli). The transient nature of α-Synoli complicates in vivo studies, and while their toxicity is well-documented in biophysical and cellular models, it has not been successfully replicated in living organisms. Recently, dopamine-stabilized α-Syn oligomers (DA-α-Synoli) were characterized through in vitro and ex vivo studies, revealing a critical interaction between dopamine and α-Syn in driving toxicity, underscoring the relevance of oligomers in disease pathology.
Here, we developed a novel in vivo model of oligomer toxicity using the nematode Caenorhabditis elegans. This model employed a transgenic strain of C. elegans that overexpresses human α-Syn in GFP-labeled dopaminergic neurons, where DA-α-Synoli induce neurodegeneration. We challenged the model with oligomers formed in the presence of DAD9, a novel small molecule developed by our group that conjugates dopamine with a non-antibiotic tetracycline (TC). In cell-based assays, DAD9 generates fewer toxic species compared to DA-α-Synoli. Our findings demonstrate that this in vivo model is a valuable tool for investigating the toxicity of various α-Syn species and for assessing small molecules that may disrupt neurodegenerative processes, offering promising therapeutic avenues against synucleinopathies.