Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice

Venkatesh, Aditya; Ma, Shan; Le, Yun Zheng; Hall, Michael N.; Rüegg, Markus A.; Punzo, Claudio

doi:10.1172/jci79766

Cited by 140 publications

(233 citation statements)

References 62 publications

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“…This finding builds off the work of groups like Punzo et al, who found metabolic aberrations in the insulin/mTOR signalling pathway in the cones of four different mouse models of RP. Systemic treatment with insulin encouraged cone survival, suggesting that there may be a metabolic basis to retinal degeneration in these models (21,29). Our paper advances these findings by corroborating their cone results in rods and identifying a potential mechanism to explain how mTOR upregulation promotes anabolism.…”

Section: Discussionsupporting

confidence: 67%

“…This is supported by previous studies. GLUT1 has been shown to play a pivotal role in cone protection by TSC2 ablation, which enhanced the mTOR pathway (29). Additionally, GLUT1 is an essential component for rod Immunoblot revealed upregulated mTOR, p-mTOR, pS6, GLUT1, and p4EBP1 expression levels and downregulated TSC1 levels in the experimental versus control groups.…”

Section: Discussionmentioning

confidence: 98%

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Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Zhang

Justus

et al. 2016

Hum. Mol. Genet.

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Retinitis pigmentosa (RP) is an incurable neurodegenerative condition featuring photoreceptor death that leads to blindness. Currently, there is no approved therapeutic for photoreceptor degenerative conditions like RP and atrophic age-related macular degeneration (AMD). Although there are promising results in human gene therapy, RP is a genetically diverse disorder, such that gene-specific therapies would be practical in a small fraction of patients with RP. Here, we explore a non-genespecific strategy that entails reprogramming photoreceptors towards anabolism by upregulating the mechanistic target of rapamycin (mTOR) pathway. We conditionally ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6b H620Q/H620Q preclinical RP mouse model and observed, functionally and morphologically, an improvement in the survival of rods and cones at early and late disease stages. These results elucidate the ability of reprogramming the metabolome to slow photoreceptor degeneration. This strategy may also be applicable to a wider range of neurodegenerative diseases, as enhancement of nutrient uptake is not gene-specific and is implicated in multiple pathologies. Enhancing

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 98%

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Zhang

Justus

et al. 2016

Hum. Mol. Genet.

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“…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)(47)(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.…”

Section: Resultsmentioning

confidence: 99%

“…Normally, the OS of photoreceptors are continuously regenerated in a process that requires NADPH from the pentose phosphate pathway (PPP) to generate phospholipids (11,12). Rods shuttle glucose into the PPP to synthesize new membranes and facilitate OS generation (13,14).…”

Section: H620q/h620qmentioning

confidence: 99%

“…In one study, injection of insulin in 4 unique RP mouse models was shown to delay degeneration of cones, and increased levels of GLUT1 and HIF1A were detected (11). In another study involving tuberous sclerosis complex 2 (TSC2) ablation, the mTOR pathway was enhanced, leading to upregulation of GLUT1, which was hypothesized to protect cones from degeneration (12). Additionally, GLUT1 was shown to play an important role in protecting rods via rod-derived cone viability factor (RdCVF) (69).…”

Section: Pde6bmentioning

confidence: 99%

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Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

111

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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...

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The Survival of Cone Photoreceptors in Retinitis Pigmentosa

Wong

Kwok²

2016

JAMA Ophthalmol

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Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice

Cited by 140 publications

References 62 publications

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

The Survival of Cone Photoreceptors in Retinitis Pigmentosa

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