Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration
Lijuan Zhang, … , James B. Hurley, Stephen H. Tsang
Lijuan Zhang, … , James B. Hurley, Stephen H. Tsang
Published November 14, 2016
Citation Information: J Clin Invest. 2016;126(12):4659-4673. https://doi.org/10.1172/JCI86905.
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Research Article Genetics

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 Ca2+, 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.

Authors

Lijuan Zhang, Jianhai Du, Sally Justus, Chun-Wei Hsu, Luis Bonet-Ponce, Wen-Hsuan Wu, Yi-Ting Tsai, Wei-Pu Wu, Yading Jia, Jimmy K. Duong, Vinit B. Mahajan, Chyuan-Sheng Lin, Shuang Wang, James B. Hurley, Stephen H. Tsang

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Figure 1

Sirt6 deficiency improves electrophysiological function in both rods and cones.

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Sirt6 deficiency improves electrophysiological function in both rods an...
(A) ERG was obtained weekly under dark- and light-adapted conditions to acquire scotopic, photopic, and mixed rod-cone b-wave amplitudes (μV). Linear mixed models were fit to estimate the trajectory of outcomes over time, and differences were assessed by likelihood ratio tests. Gray and light red lines represent individual eyes; solid black and dashed red lines represent mean trajectories from the mixed models for Sirt6loxP/loxPPde6bH620Q/H620Q and Sirt6–/–Pde6bH620Q/H620Q, respectively. Sirt6–/–Pde6bH620Q/H620Q mice had higher trajectories compared with control mice for each outcome: mixed (P < 0.001), photopic (P = 0.048), and scotopic (P = 0.004). For Sirt6loxP/loxPPde6bH620Q/H620Q: at 4 weeks, n = 7; 5 weeks, n = 6; 6 weeks, n = 5; 7 weeks, n = 5; 8 weeks, n = 3. For Sirt6–/–Pde6bH620Q/H620Q: at 4 weeks, n = 5; 5 weeks, n = 6; 6 weeks, n = 7; 7 weeks, n = 9; 8 weeks, n = 5; 10 weeks, n = 3. (B) Comparison of ERG data under scotopic, photopic, and mixed conditions at 4, 6, and 8 weeks. Gray dots and light red triangles represent data from individual mice; black dots and red triangles are means for Sirt6loxP/loxPPde6bH620Q/H620Q and Sirt6–/–Pde6bH620Q/H620Q, respectively. There were significant differences between the groups at all time points and all light adaptation conditions except for photopic conditions at 4 weeks and scotopic at 8 weeks. A linear mixed model was fit to compare groups. At 4 weeks: scotopic b-wave P = 0.004, mixed b-wave P = 0.01, photopic b-wave P = 0.3; 6 weeks: scotopic b-wave P = 0.007, mixed b-wave P < 0.001, photopic b-wave P = 0.003; 8 weeks: scotopic b-wave P = 0.2, mixed b-wave P < 0.001, photopic b-wave P = 0.048. *P < 0.05, **P < 0.01, and ***P < 0.001.