Language
English
Publication Date
6-5-2024
Journal
Molecular Therapy
DOI
10.1016/j.ymthe.2024.04.030
PMID
38659223
PMCID
PMC11184404
PubMedCentral® Posted Date
4-24-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level was decreased after IOP elevation. Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons, whereas partial or RGC-specific Sirt6 deletion accelerated RGC loss. Importantly, therapeutically targeting Sirt6 with pharmacological activator or AAV2-mediated gene delivery ameliorated high IOP-induced RGC degeneration. Together, our studies reveal a critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma, setting the stage for further exploration of Sirt6 activation as a potential therapy for glaucoma.
Keywords
Animals, Retinal Ganglion Cells, Mice, Sirtuins, Glaucoma, Optic Nerve, Aging, Disease Models, Animal, Intraocular Pressure, Humans, Axons, Mice, Knockout, Nerve Degeneration, glaucoma, aging, Sirt6, retinal ganglion cells, optic nerve, neurodegeneration, AAV2, Sirt6 activator
Published Open-Access
yes
Recommended Citation
Xia, Fan; Shi, Shuizhen; Palacios, Erick; et al., "Sirt6 Protects Retinal Ganglion Cells and Optic Nerve From Degeneration During Aging and Glaucoma" (2024). Faculty and Staff Publications. 3958.
https://digitalcommons.library.tmc.edu/baylor_docs/3958