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 3

Sirt6 deficiency promotes photoreceptor survival and preserves cellular OS.

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Sirt6 deficiency promotes photoreceptor survival and preserves cellular...
(A and B) Rhodopsin antibody staining of retinal OS layers was used to compare morphological differences between control and treated mice. The expression of rhodopsin was greater in the Sirt6–/–Pde6bH620Q/H620Q mice at every time point. (B) Gray dots represent data from individual Sirt6loxP/loxPPde6bH620Q/H620Q mice, and a black trend line was projected to connect the means at each time point. Light red triangles represent data from individual Sirt6–/–Pde6bH620Q/H620Q mice, and the red dashed line represents a projected trendline to connect the means for the Sirt6–/–Pde6bH620Q/H620Q mice at each time point. Two-tailed t tests were used to analyze the data. 3 weeks: P = 0.012; 4 weeks: P = 0.002; 6 weeks: P < 0.001. n = 5 per group at all time points. Scale bars: 20 μm throughout figure (A, C, and E). (C and D) Short-wavelength cone opsin antibody (blue) staining of retinal OS layers allowed comparison of morphological differences. The OS of cones were elongated in treated mice. (D) Graphical representations and statistical analyses are as indicated in A and B. 3 weeks: P < 0.001; 4 weeks: P = 0.001; 6 weeks: P < 0.001. n = 5 per group at all time points. (E and F) DAPI (blue) and anti–cone arrestin (green) staining allowed visualization of retina nuclei and cone cell markers, respectively. Results were merged into composite images. Cone density (nuclei/0.0025 mm2) was greater in the Sirt6-knockout mice at every time point compared with controls. (F) Graphical representations and statistical analyses are as indicated in A and B. P < 0.001 at 4, 6, 8, and 10 weeks; P = 0.0016 at 12 weeks. For Sirt6loxP/loxPPde6bH620Q/H620Q: n = 3 at all time points; for Sirt6–/–Pde6bH620Q/H620Q: n = 4 at all time points. *P < 0.05, **P < 0.01, and ***P < 0.001.