Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Abstract

Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca 2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration , were challenging to interpret because of negative effects on synaptic transmission (45). We therefore altered our approach to limit ablation of Sirt6 to rod photoreceptors with an inducible gene disruption strategy. Using this model, we tested whether upregulation of glycolytic flux through Sirt6 knockout can preserve both rod and cone photoreceptors in a preclinical, Pde6-associated RP model. The Journal of Clinical Investigation R E S E A R C H A R T I C L E ResultsGeneration of experimental and control groups. The third most common cause of autosomal recessive RP is deficiency in the PDE6 enzyme, which controls the depolarization state of rods by regulating cGMP levels (9, 46-48). An established preclinical model for RP involves a homozygous point mutation (H620Q) in the gene months by increasing glucose uptake and utilization for NADPH production in 4 different mouse models of RP (11,12). In our report, we propose a similar strategy that improves both survival and function of degenerating rods and cones. We hypothesized that Pde6-associated RP provokes a metabolic aberration in the rod cells that forces them to succumb to the consequences of elevated cGMP and Ca 2+ via cyclic nucleotide-gated (CNG) channels and Na + /Ca 2+ -K + exchangers (36-39). The histone deacetylase sirtuin 6 (SIRT6) is a transcriptional repressor of glycolytic enzymes that has been extensively studied in the context of metabolism and cancer biology (40). Normally, S...

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.…”

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

“…A potential therapeutic approach for RP is to reprogram metabolic pathways that are altered during rod dystrophy and RP progression. In one such approach, we found that knocking down sirtuin-6 (SIRT6) to reprogram retinal cells toward anabolism delayed photoreceptor cell degeneration in a mouse model of RP [24]. For this study, we applied a liquid biopsy proteomics approach to identify the molecular pathway targets affected during RP progression.…”

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

“…Cone photoreceptors are indispensable for human vision in daylight and their loss in inherited or acquired retinal diseases have devastating effects on daily tasks and life quality (27,45,46).…”

“…Aberrant HDAC activity is causatively linked to various diseases ranging from cancer, through muscular dystrophies, to neurodegenerative diseases (22,23). We and others have previously shown that regulation of epigenetic patterns, via HDAC inhibition can protect primary degenerating photoreceptors in inherited retinal dystrophies caused by mutations in different genes (24)(25)(26)(27)(28). Consequently, more than 90 clinical trials involving HDAC regulators stress HDAC inhibition as promising therapeutic approach for various diseases including retinal dystrophies (21,29).…”