POLYSTYRENE NANOPLASTICS AS MODULATORS OF ALPHA-SYNUCLEIN ACCUMULATION IN PARKINSON’S DISEASE MODELS

Parkinson’s disease (PD) is a largely sporadic neurodegenerative disorder, highlighting an important contribution of environmental factors to disease susceptibility and progression. Core pathological hallmarks of PD include dopaminergic neurodegeneration and the accumulation and aggregation of α-synuclein (αSyn) within neurons. Increasing environmental exposure to polystyrene nanoplastics (PS-NPs) has raised concerns regarding their potential impact on brain health; however, their relevance to PD-associated pathology remains poorly understood. Here, we investigated neuronal susceptibility to environmental stressors using human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons from healthy donors. Neurons were exposed to PS-NPs with distinct surface charges, αSyn pre-formed fibrils, or varying concentrations of the dopaminergic neurotoxin MPP⁺ (1-methyl-4-phenylpyridinium). We assessed cell viability, nanoparticle uptake (object fluorescence intensity), and total and aggregated αSyn levels using immunofluorescence-based analyses. Initial findings identified 10 μg/ml anionic PS-NPs as the optimal exposure condition, demonstrating efficient neuronal uptake and increased total αSyn intensity without overt cytotoxicity, as observed at 50 μg/ml. Sequential exposure experiments revealed a synergistic effect between anionic PS-NPs and αSyn PFFs, resulting in enhanced neuronal αSyn uptake and significantly higher aggregated αSyn levels than with PFF treatment alone. This co-exposure paradigm was associated with increased cytotoxicity by day 7. In contrast, although high-dose MPP⁺ (4 mM) induced pronounced neuronal death and network disruption, it did not significantly alter total or aggregated αSyn levels. Ongoing studies aim to elucidate the molecular mechanisms by which nanoplastic exposure modulates αSyn pathology and neuronal vulnerability, providing insight into how emerging environmental pollutants may contribute to PD-related neurodegenerative processes.