SPIONs AS MODULATORS OF ALPHA-SYNUCLEIN AGGREGATION AND TOXICITY: PROMISING IMPLICATIONS FOR NEUROPROTECTION IN PARKINSON'S DISEASE

Introduction: Parkinson's disease, one of the major neurodegenerative disorders, predominantly affects individuals over the age of 60. Characterized by the death of dopaminergic neurons in the substantia nigra and the presence of protein aggregates called Lewy bodies, with alpha-synuclein as their main constituent, understanding the mechanisms of alpha-synuclein aggregation through in vitro studies provides valuable insights for the development of molecules capable of modulating this aggregation and acting as neuroprotective agents, inhibiting the toxicity of the aggregated species. This approach may prevent cell death and preserve neuronal morphology and viability. Objective: This study aims to investigate the effect of superparamagnetic iron oxide nanoparticles (SPIONs) on alpha-synuclein aggregation and its toxicity in neuroblastoma cells, highlighting their potential as neuroprotective therapeutic agents. Methodology: Lyophilized alpha-synuclein was diluted in phosphate-buffered saline (PBS) to a final concentration of 140 µM and subjected to aggregation conditions (37°C, constant agitation, pH 7.4). Aggregation was monitored using thioflavin T, scanning electron microscopy in STEM mode, and SPION internalization was evaluated through Prussian blue staining. Viability assays, DNA fragmentation, mitochondrial membrane potential loss, and quantification of reactive oxygen species were also performed in SH-SY5Y neuroblastoma cells after 24 hours of SPION treatment. Results: The results of this study indicate that the presence of SPIONs delays the formation of alpha-synuclein oligomers and inhibits fibril formation, as observed by the aggregation kinetics. Scanning electron microscopy analysis revealed that alpha-synuclein with SPIONs showed fewer but more structured and fragmented aggregates compared to pure alpha-synuclein. Cell viability assays demonstrated that SPIONs do not affect cell survival. Moreover, toxic oligomers formed in the presence of SPIONs exhibited reduced toxicity to cultured cells. The cells were able to internalize SPIONs, distributing them randomly throughout the cytoplasm depending on the concentration. SPION presence reduced DNA fragmentation and mitochondrial damage, preserving cell viability and reducing oxidative stress. Conclusion: Based on the obtained results, it can be inferred that SPIONs have the ability to modulate alpha-synuclein aggregation and toxicity. These findings suggest that SPIONs could be explored as potential therapeutics and play a neuroprotective role.