Regulation of the p62 promoter by oxidative damage in neurodegenerative disease and aging

Abstract

Oxidative stress is regarded as the damage to a biological system caused by reactive oxygen species (ROS) when the prooxidant overwhelms the antioxidant defense and repair ability. Growing evidence reveals that oxidative stress is a major contributor to aging and neurodegeneration. P62 is a scaffold protein that is utilized for cell signaling, receptor trafficking, and inclusion formation. P62 knockout mice exhibit Alzheimer’s Disease-like phenotype. The structure and function of p62, ROS formation and oxidative damage to macromolecules, the antioxidant defense system, the relationship among p62, oxidative stress, aging, and neurodegenerative disease were reviewed in Chapter I. Declined p62 expression levels were observed in Alzheimer’s Disease (AD) brains compared to tissue from normal individuals. My hypothesis was that reduced p62 level might be caused by oxidative damage to the p62 promoter. In order to test this hypothesis, two specific objectives were undertaken: (1) examine age-associated oxidative damage to the p62 promoter in AD; (2) examine whether this damage is common in various neurodegenerative disease. In Chapter II, we showed that oxidative damage to the p62 promoter was significantly higher in DNA from AD brain than normal brain. Also, this damage was age-dependent in both WT mice and normal brains. The negative correlation between oxidative damage to the p62 promoter and the p62 expression level was demonstrated in human brains, mice, and HEK cells. In Chapter III, we showed that no genetic variance was found between the p62 promoter in normal and diseased brains. However, oxidative damage to the p62 promoter was significantly higher in various neurodegenerative diseases than normal brains. Decreased activity and induction of the p62 promoter were caused by oxidative damage to the p62 promoter and the deletion of Sp-1 binding site. Altogether, these findings revealed that p62 level was regulated by oxidative damage to the p62 promoter. P62 regulation and future works were summarized in Chapter IV. Proteasome or autophagy inhibition up-regulates p62 protein levels. Decreased p62 level results in the reduced delivery of substrate to autophagy, leading to more damaged organelles. Since p62 knockout mice showed higher oxidative stress, the mechanism leading to this result will be further investigated and mitochondria dysfunction will be examined in WT, p62 knockout, and p62 over-expressed mice.