Oxidative Stress and the Ubiquitin Proteolytic System in Age-Related Macular Degeneration

Abstract

AMD is a leading cause of irreversible vision loss in people over 60 years of age. Although the pathogenesis of this disease is multifactorial, clinical studies have revealed that oxidative damage is a significant etiological factor. The ubiquitin proteolytic system (UPS) plays a major cytoprotective role in the retina. It accomplishes this largely by degrading oxidatively-damaged proteins to prevent their toxic accumulation. In this review, we discuss numerous features of the UPS in the retina and propose various ways that components of the UPS can be harnessed for therapeutic intervention in AMD. We discuss published work describing the distribution of various UPS enzymes in different retinal cell types and present new findings describing the localization of the class III ubiquitin conjugating enzymes. These enzymes are functional homologues of a pair of yeast enzymes that mediate the degradation of misfolded and oxidatively-damaged proteins. We also discuss recent work showing that only newly synthesized proteins which have incurred oxidative damage are targeted for degradation by the UPS whereas the turnover of oxidatively-damaged, long-lived proteins is largely unchanged. Additionally, we review recent work describing how polyubiquitylation influences the sorting of damaged proteins into one of two novel intracellular compartments. Finally, we discuss how the UPS modulates the stability and activity of Nrf2, the major anti-oxidant transcription factor in the retina.