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A metabolic approach for retinal degeneration

Retinitis pigmentosa (RP) is a heterogeneous genetic disorder that is characterized by a progressive loss of photoreceptors that results in deterioration of vision.  While gene therapy has shown promise for some forms of RP, over 60 genes have been implicated in this disorder; therefore, non-gene-targeted therapies are of great interest.  In this episode, Stephen Tsang and colleagues discuss their study, which shows that upregulation of glycolytic flux, via targeted downregulation of sirtuin 6, in rod photoreceptors improves photoreceptor survival and preserves vision in a mouse model of RP. As this strategy is not gene-specific, it may be beneficial for a range of neurodegenerative disorders. 

Published November 14, 2016, by Corinne Williams

Author's Take

Related articles

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 December 1, 2016; First published November 14, 2016
Citation Information: J Clin Invest. 2016;126(12):4659-4673. https://doi.org/10.1172/JCI86905.
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Categories: Research Article Genetics Therapeutics

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

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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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