Degenerative diseases of the retina are caused by ~4,500 distinct mutations in more than 250 genes. Such incredible genetic diversity suggests that the most useful therapeutic interventions would target common pathobiological pathways. In our previous work, we have demonstrated that insufficient ubiquitin- proteasome activity contributes to photoreceptor loss in several forms of retinal degenerations. More recently, we have discovered that an increase in proteolytic capacity of photoreceptors improves their survival during retinal degeneration. Therefore, our studies have established the ubiquitin-proteasome system as a promising therapeutic target. The ubiquitin-proteasome system (UPS) is a complex fine-tuned cellular network composed of several hundreds of different proteins working in concert with chaperone and autophagy systems. One of the most efficient strategies to manipulate such complex cellular systems is to target transcriptional factor(s) or pathways controlling the expression levels of its key components. In this proposal we will identify pathways governing transcriptional control of proteasomal biogenesis in photoreceptors in coordinated manner. Specifically, we will explore the role of two regulators of proteasome biogenesis, mTOR and NFE2L1, in rod photoreceptors in mice. Our studies will employ genetic approaches to stimulate NFE2L1 and mTOR pathways. We will use multiple methods to study how stimulation of these pathways affects ubiquitin-proteasome system, autophagy and translation. We will investigate the impact of these pathways on two independent models of retinitis pigmentosa. Understanding mechanisms of proteostasis regulation in photoreceptors would provide insights into therapeutic potential to manipulate these pathways in the future studies.
Retinal degenerations cause irreversible loss of vision, restrict all aspects of daily living and substantially reduce the quality of life. The exceptional genetic heterogeneity of retinal degenerations necessitates years of development of individual treatments and consumes significant resources. Studies in multiple experimental systems have demonstrated that an increase in proteolytic capacity of post-mitotic cells is non-toxic, increases cellular resistance to a variety of stressors, delays cellular aging and senescence. Therefore, approaches to stimulate proteolytic activity in retinal cells could have therapeutic potential for a broad range of retinal degenerations, not necessarily associated with protein misfolding. This study seeks to define principal pathways responsible for processing damaged proteins in cells, which could be manipulated to treat retinal diseases in both mutation- and gene-independent manner, thus accelerating delivery of treatments to the patients.