1. Academic Validation
  2. Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma

Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma

  • Mol Ther. 2024 Apr 24:S1525-0016(24)00253-3. doi: 10.1016/j.ymthe.2024.04.030.
Fan Xia 1 Shuizhen Shi 1 Erick Palacios 1 Wei Liu 1 Seth E Buscho 1 Joseph Li 1 Shixia Huang 2 Gianmarco Vizzeri 1 Xiaocheng Charlie Dong 3 Massoud Motamedi 1 Wenbo Zhang 4 Hua Liu 5
Affiliations

Affiliations

  • 1 Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 2 Advanced Technology Cores, Department of Molecular and Cellular Biology, Department of Education, Innovation and Technology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 4 Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Neurobiology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: we2zhang@utmb.edu.
  • 5 Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: hualiu@utmb.edu.
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

AAV2; Sirt6; Sirt6 activator; aging; glaucoma; neurodegeneration; optic nerve; retinal ganglion cells.

Figures
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  • HY-D0985A
    98.70%, Mitochondrial Membrane Potential Fluorescent Dye