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Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of Lewy bodies, which are intracellular inclusions primarily composed of aggregated α-synuclein. While genetic mutations contribute to familial forms of PD, mounting evidence suggests a multifactorial etiology involving the interplay of genetic susceptibility and environmental factors, such as exposure to pesticides and heavy metals. Many individuals are routinely exposed to metal mixtures in specific occupational environments, such as welding, where the inhaled fumes contain manganese (Mn), a well-established neurotoxicant, along with other metals, including vanadium (V). Epidemiological studies have shown that farmers exposed to pesticides and welders exposed to metal fumes face an elevated risk of developing PD. This dissertation investigates gene-environment interactions by co-exposing a transgenic mouse model of PD that overexpresses the A53T mutant form of human α-synuclein to Mn and V. Chronic co-exposure to these metals exacerbated PD-like neurobehavioral symptoms, including motor and olfactory deficits, in A53T transgenic mice, with males showing more pronounced effects. These findings suggest a synergistic neurotoxic effect of Mn and V and a potential sex-specific vulnerability. In parallel, serum-derived neuronally enriched extracellular vesicles (EVs) from asymptomatic welders showed dysregulated miRNAs. Specifically, miR-16-5p, miR-93-5p, and miR-486-5p correlated with multiple blood metal levels and exposure metrics, underscoring their potential as minimally invasive biomarkers for early PD detection and monitoring. Moreover, elevated levels of extracellular histones, particularly histone H3, were identified in EVs from serum samples of PD patients, pesticide-exposed farmers, and a mouse model of PD, as well as in EVs from PD cell models. Recombinant (r)H3 activated the NLRP3 inflammasome in microglial cells through the Fyn kinase signaling pathway, resulting in the generation of reactive oxygen and reactive nitrogen species and the release of proinflammatory cytokines. In addition, rH3 also amplified α-synuclein aggregation, further exacerbating the neuroinflammatory cascade. Together, these findings reveal novel mechanisms involved in PD pathogenesis and highlight the potential of serum-derived EV-enclosed histones and miRNAs as promising biomarkers for early diagnosis and disease progression.