TARGETED DEGRADATION OF ΑLPHA-SYNUCLEIN LIMITS PATHOLOGICAL AGGREGATION IN A CELLULAR MODEL OF PARKINSON’S DISEASE

Parkinson's disease is a progressive neurodegenerative disorder characterized by the accumulation of pathological aggregates of α-synuclein, a molecular hallmark of synucleopathies, in neurons. α-Synuclein contributes to the selective degeneration of dopaminergic neurons in the substantia nigra, leading to severely disabling motor and non-motor symptoms. Despite major advances in the understanding of pathophysiological mechanisms, current therapeutic options remain mainly symptomatic, highlighting the need for strategies that directly target the molecular determinants of the disease. In this study, we evaluated the therapeutic potential of protein degraders-targeting α-synuclein in a cellular model of Parkinson's disease based on HEK293 cells overexpressing the A53T mutant form of α-synuclein, and treated with preformed fibrils (PFFs) to replicate the intracellular accumulation of aggregated α-synuclein found in vivo. Western-blot and immunocytochemistry analysis revealed that 2 of our α-synuclein-degraders produced a reproducible reduction in monomeric α-synuclein at 24h post-treatment and in high molecular weight aggregates at 48h post-treatment associated with a rebound in the monomeric forms of the protein. The observed effects were time-dependent with measurable efficacy in the low micromolar range (0.1µM), suggesting a potent efficacy in modulating pathological protein load. Taken together, these findings identified targeted degradation of α-synuclein as a promising therapeutic strategy and highlighted these α-synuclein-degraders as attractive candidates for further investigations. However, further in vitro and in vivo validation will be essential to assess their efficacy, specificity and pharmacokinetic properties, brain penetrance, and safety, and to determine their true potential as disease-modifying agents in synucleinopathies.