ABSTRACT

Parkinson's disease (PD) is a progressive neurodegenerative disease, causing severe dopamine depletion in the striatum. Evidence shows that iron dyshomeostasis contributes to PD. Our long term goal is to improve the understanding of iron associated PD, thereby pave the way for nutritional prevention against PD in clinical trials. In this dissertation, the overarching hypotheses were that the neurotoxin 6-OHDA caused iron dyshomeostasis by regulating iron-related factors, increasing oxidative damage to neuron cells, while the iron chelator EGCG could counteract these adverse effects and prevent PD.

PD model cells are used to study the mechanism on disruption of iron metabolism by 6-OHDA in vitro. In the first study, we determined that 6-OHDA caused iron dyshomeostasis in N27 cells by regulating iron transporters and regulators expression, such as DMT1, TfR, and hepcidin. We have direct evidence showing 6-OHDA caused iron burden by ⁵⁵Fe iron uptake assay. 6-OHDA also caused primary neuron cell death. However, we confirmed that EGCG protected against 6-OHDA induced neurotoxicity. EGCG reduced the intracellular iron retention by decreasing the iron importers and increasing iron exporters, such as Fpn1. In the second study, we further confirmed that increased iron by 6-OHDA augmented ROS generation and caused oxidative damage to lipid and protein in vitro. The increased activities of antioxidant and anti-inflammatory system, including Nrf2, HO-1, and PPARγ, suggested the increased oxidation and inflammation. However, EGCG attenuated ROS generation, reduced oxidative stress, and blocked the consequential antioxidant and anti-inflammatory reactions. Since EGCG is the most abundant polyphenol and iron chelator present in green tea, it may offer a prospective dietary approach to protect PD patients. In the third study, we hypothesized that green tea consumption may be beneficial for PD patients. We have shown that an intervention of 3 cups of green tea daily for 3 months improved the antioxidant status and reduced oxidative damage in early PD patients without affecting their iron status.

In summary, the findings in this project reveal the importance of iron regulation in PD progression and that the beneficial effects of EGCG act as a promising preventive approach for PD both in vitro and in vivo.