TRANSLATIONAL IMPACT

Abstract

Oxidative stress is associated with a plethora of human diseases, aging manifestations and metabolic deficits. Regardless of the etiology, the biological and pathological effects of oxidative stress are linked to dysregulation of various signaling pathways and subcellular processes, such as mitochondrial dysfunction, toxicity caused by the accumulation of metabolic byproducts and impaired functioning of detoxifying subcellular machineries such as the ubiquitin-proteasome system. Accumulating evidence indicates that different populations of neurons show differential vulnerabilities and responses to oxidative stress. In addition, mutations in a widely expressed gene can alter the vulnerability of select neuronal cell types to oxidative stress and can promote neurodegeneration. The identification and characterization of factors and processes that suppress the deleterious effects of oxidative stress can provide insight into mechanisms of neuroprotection and uncover novel therapeutic targets by which the clinical manifestations of various diseases and aging can be modulated.Light-elicited oxidative stress is a deleterious risk factor linked to retinal dystrophies, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), which occur owing to the selective degeneration of abundant photoreceptor neurons of the retina. In this work, the authors explore the molecular effects of insufficiency of RAN-binding protein-2 (RANBP2) in protecting photoreceptors and the supporting tissue, the retinal pigment epithelium (RPE), from degeneration induced by light-elicited oxidative stress. By contrasting molecular and subcellular phenotypes of retina and RPE in inbred wild-type and Ranbp2-haploinsufficient mice in the absence or presence of light-elicited oxidative stress, the authors show that the expression levels of a subset of functionally diverse partners of RANBP2 – such as RAN GTPase, UBC9, subunits of the 26S proteasome and a set of orphan nuclear receptors – are differentially modulated by Ranbp2 haploinsufficiency and oxidative stress in the retina. The effects of oxidative stress are also accompanied in Ranbp2-haploinsufficient mice by a decrease in the levels of ubiquitylated proteins, thereby supporting the notion that insufficiency of RANBP2 relieves the suppressive effect of this protein on the activity of the 26S proteasome in the presence of oxidative stress. Strikingly, the authors also find that the formation of lipid deposits induced by oxidative stress in the RPE – a hallmark of many neurodegenerative diseases and aging – is strongly suppressed by Ranbp2 haploinsufficiency. However, in contrast to effects in the retina, the expression levels of most RANBP2 partners are not affected in the RPE.This study establishes a cell-context dependent and direct link between RANBP2, a subset of its binding partners, light-elicited oxidative stress and associated pathological manifestations. These data have multiple implications. First, they establish the Ranbp2-haploinsufficient mouse model as a useful tool to study the roles of oxidative signaling pathways and various stressors in the context of aging, neurodegeneration and other diseases that affect photoreceptors. Second, these data might help to unravel the roles of various stressors in other neuronal cell types with differential susceptibility to oxidative stress. Finally, determining the cell-context-dependent effects of the subunits of the pleiotropic complex that is regulated and assembled by RANBP2 will help to unravel further the complexity of responses underpinning stress-signaling pathways, and contribute to developing novel therapeutic approaches to targets with neuroprotective properties.