Abstract Background: While alpha-synuclein (alpha-syn) accumulation and iron dysregulation are hallmarks of Parkinson's Disease, the adaptations that enable neuronal survival under chronic protein stress remain unclear. Here, we investigated how alpha-syn overexpression and ceruloplasmin (Cp)-mediated iron modulation alters iron and redox homeostasis. Methods: We utilized human BE(2)-M17 neuroblastoma cell lines stably expressing different levels of alpha-syn to examine the interplay between alpha-syn, Ceruloplasmin (Cp)-mediated iron modulation, and the cellular response to oxidative stress. Analyses included Western blotting, immunofluorescence staining, soluble/insoluble fractionation, glutathione, reactive oxygen species (ROS) and hydrogen peroxide (H2O2) quantification, lipid peroxidation, ferrous iron, and cell viability. Results: Our data suggest an unexpected relationship between chronic alpha-syn expression and cellular redox regulation. Despite carrying a greater alpha-syn burden, cells with higher alpha-syn expression exhibit lower basal ROS, H2O2, and lipid peroxidation compared to control cells. These changes are not accompanied by activation of canonical antioxidant pathways suggesting that the reduced oxidative profile arises through alternative mechanisms. Besides, alpha-syn over-expressing cells display significant remodeling of iron-handling pathways, including altered expression of ferritin heavy chain, transferrin receptor, and ferroportin, suggesting that chronically high alpha-syn levels are associated with changes in iron homeostasis. In addition, this phenotype is not maintained following Cp overexpression. Although Cp reduces Fe2+ levels, it also induces substantial increases in ROS and H2O2; without corresponding changes in GPX4, glutathione, or related antioxidant systems. Thus, the reduced basal oxidative profile observed in alpha-syn-over-expressing cells does not reflect enhanced canonical antioxidant capacity. Instead, chronically high alpha-syn levels appear to be associated with adaptive remodeling of iron and redox pathways that become sensitive to oxidative imbalance. Conclusion: Chronic alpha-syn over-expression promotes adaptive remodeling of iron and redox homeostasis, associated with reduced basal oxidative stress but increased sensitivity to Cp-mediated perturbation. These data link alpha-syn burden to iron metabolism and stress-dependent vulnerability in synucleinopathies.
Pourhadi, M., Ranxhi, B., Sukaria, S. P., Hussein, F. H., Todi, S. V., LeWitt, P. A., Tsou, W.-L.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 2
- Comments 0