title: 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.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.forename: Jianhai
authors.initials: J
authors.lastname: Du
authors.forename: Sally
authors.initials: S
authors.lastname: Justus
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Hsu
authors.forename: Luis
authors.initials: L
authors.lastname: Bonet-Ponce
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Wu
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tsai
authors.forename: Wei-Pu
authors.initials: WP
authors.lastname: Wu
authors.forename: Yading
authors.initials: Y
authors.lastname: Jia
authors.forename: Jimmy K
authors.initials: JK
authors.lastname: Duong
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: James B
authors.initials: JB
authors.lastname: Hurley
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D000067470:Cellular Reprogramming Techniques / Q000379:methods*; D002952:Citric Acid Cycle / Q000235:genetics; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006019:Glycolysis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D005136:Eye Proteins; C501860:Sirt6 protein, mouse; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D037761:Sirtuins; D006152:Cyclic GMP