Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

Abstract

Most Retinitis Pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nightime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE), and thus is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment -rich outer segments (OS), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis.

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

“…For example, retinal genetic rescue at advanced disease stages does not lead to OS regeneration (5,18,19), suggesting a correlation between photoreceptor numbers and OS synthesis. Perhaps a critical number of rods might be needed to release glucose from RPE, where it is sequestered following rod degeneration and thus unavailable to support OS synthesis (8,20). Interestingly, in untreated RP patients (and mice), the earliest detected histopathologic change is rod OS dysgenesis.…”

“…In addition, the arrestin immunolabeling revealed dramatic dose-dependent rescue of cones-especially cone OS length. The small amount of arrestin immunolabeling in mutant retinas represents the fraction of cone cells-devoid of their OSs-that persist for some time after mutant rods have died (8).…”

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…While cell culture models suggest high glycolytic rates in RPE, it is thought that RPE preferentially passes glucose to the photoreceptors (Strauss, 2005). Supporting this notion, the RPE express low levels of hexokinase, which would allow glucose to pass through as opposed to entering glycolysis to be consumed in the RPE (Lowry et al, 1961; Wang et al, 2016). Kurihara et al have shown that increasing glycolytic rates in RPE may lead to photoreceptor degeneration.…”

Swine models, genomic tools and services to enhance our understanding of human health and diseases

“…Another advantage of this pig model is that the inbred miniature pig genetic background facilitates the development of cell-based therapies. Researchers can inject large volumes of inoculum into the pig eye, allowing them to study the effects of cell-based therapies without any confounding effects of rejection 14 . This model has been used for several experiments, such as determining whether the dietary supplement curcumin can arrest or delay rod photoreceptor degeneration 15 .…”