Micro- and Nanoplastics Exposure and Parkinson’s Disease: Insights from Human Stem Cell Derived Cells and Midbrain Organoid Models

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease, characterized by the mass death of dopaminergic neurons in the midbrain. Neuroinflammation is posited as a key driver of neurodegeneration, through the chronic activation of immune cells. Microglia are the brain’s resident immune cells and are heavily implicated in neuroinflammation. Toxicant exposure is an environmental factor that is believed to contribute to apoptosis through increased cytokine signaling, mitochondrial dysfunction, and alpha-synuclein aggregation. Micro- and nanoplastics (MNPs) are emergent environmental toxicants that are believed to contribute to neurodegenerative pathologies. Studies on human brain samples found significant concentrations of MNPs as compared to other vital organs (Nihart et al., 2025). Additionally, MNPs are suggested to be capable of undergoing interactions with alpha-synuclein (Liu et al., 2023). To explore the effects of MNPs exposure on neuroinflammation and dopaminergic neuron health, 2D and 3D human-induced pluripotent stem cell (hiPSC) models were utilized. The midbrain organoid model used for this thesis presented humanly relevant qualities, as it consisted of dopaminergic neurons and glial cells. Specifically, the purpose of this thesis was to determine the effect of MNPs exposure on the pro-inflammatory cytokine release, and ultimately dopaminergic neuron death. MNPs exposure to microglia cells resulted in an upward trend of IL 6 expression that was consistent with increased dosage. MNPs exposure did not affect the neural cell viability alone. In midbrain organoids, MNPs exposure resulted in an upward trend of the expression of nuclear related receptor 1 (NURR1) and carnitine palmitoyl-transferase 1A (CPT1A). NURR1 is a vital gene that mediates dopaminergic neuron maturation and differentiation. Mitochondria biosynthesis is also signaled by NURR1-related interactions. CPT1A is associated with the transport of fatty acids across the mitochondrial membrane and lipid droplet accretion. CPT1A-mediated fatty acid β-oxidation supports glial cell metabolic reprogramming and promotes pro-inflammatory activation. Based on the preliminary data generated in this study, it is suggested that MNPs exposure contributed to neuroinflammation and neurodegeneration through increased inflammatory signaling and mitochondrial metabolism. Additional investigation is needed to determine the specific cell types responsible for increased CPT1A and NURR1.