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Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration.

TitleReprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration.
Publication TypeJournal Article
Year of Publication2016
AuthorsZhang, Lijuan, Du Jianhai, Justus Sally, Hsu Chun-Wei, Bonet-Ponce Luis, Wu Wen-Hsuan, Tsai Yi-Ting, Wu Wei-Pu, Jia Yading, Duong Jimmy K., Mahajan Vinit B., Lin Chyuan-Sheng, Wang Shuang, Hurley James B., and Tsang Stephen H.
JournalJ Clin Invest
Date Published2016 Dec 01
KeywordsAnimals, Cellular Reprogramming, Cellular Reprogramming Techniques, Citric Acid Cycle, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 6, Dependovirus, Disease Models, Animal, Eye Proteins, Genetic Therapy, Glycolysis, Mice, Mice, Mutant Strains, Mutation, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Sirtuins, Transduction, Genetic

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.

Alternate JournalJ. Clin. Invest.
PubMed ID27841758
PubMed Central IDPMC5127684
Grant ListR21 AG050437 / AG / NIA NIH HHS / United States
R01 EY006641 / EY / NEI NIH HHS / United States
R01 EY018213 / EY / NEI NIH HHS / United States
R01 EY026682 / EY / NEI NIH HHS / United States
R01 EY024698 / EY / NEI NIH HHS / United States
P30 EY019007 / EY / NEI NIH HHS / United States
P30 EY001730 / EY / NEI NIH HHS / United States
R01 EY025225 / EY / NEI NIH HHS / United States
P30 CA013696 / CA / NCI NIH HHS / United States
R01 EY017863 / EY / NEI NIH HHS / United States