Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Area of Science:

• Ophthalmology
• Neuroscience
• Metabolic pathways

Background:

• Retinitis pigmentosa (RP) is a group of genetic disorders causing progressive photoreceptor degeneration and vision loss.
• The exact mechanisms driving RP photoreceptor deterioration remain unclear.
• Mutations in phosphodiesterase-6 (PDE6) are linked to RP, causing metabolic issues in rod cells due to elevated cyclic guanosine monophosphate (cGMP) and calcium (Ca2+).

Purpose of the Study:

• To investigate the role of sirtuin 6 (SIRT6) in RP pathogenesis.
• To explore the potential of inhibiting SIRT6 to restore photoreceptor function and preserve vision in RP.

Main Methods:

• Studied mouse models with Sirt6 deficiency in retinal rod cells.
• Utilized transgenic and adeno-associated virus serotype 8 (AAV2/8) gene therapy to ablate Sirt6 in rods.
• Analyzed metabolic changes, including glycolysis, TCA cycle, and glutaminolysis.
• Assessed photoreceptor survival, outer segment length, and electrophysiological function.

Main Results:

• SIRT6 inhibition reprogrammed rod cells to rely on glycolysis, increasing intermediate metabolites.
• This metabolic shift improved outer segment length and enhanced photoreceptor survival.
• Gene therapy-mediated Sirt6 ablation rescued both rod and cone photoreceptors in a preclinical RP model.
• Observed significant increases in glycolytic flux effectors and related metabolic pathways in Sirt6-deficient retinae.

Conclusions:

• SIRT6 plays a critical role in regulating photoreceptor metabolism.
• Inhibiting SIRT6 and enhancing glycolysis offers a potential therapeutic strategy for RP.
• This metabolic reprogramming approach may be applicable to various neurodegenerative disorders beyond RP.