Soluble guanylate cyclase deficiency drives retinal ganglion cell neurodegeneration with age in female mice through disrupted oxidative metabolism.

Dysfunctional cGMP signaling is implicated in multiple neurodegenerative diseases of the central nervous system (CNS), including glaucoma, an optic neuropathy and leading cause of irreversible blindness. Female mice lacking the alpha catalytic subunit of soluble guanylate cyclase (sGCα1(-/-)), the active site that binds nitric oxide (NO) to produce cGMP, exhibit progressive retinal ganglion cell (RGC) degeneration with age. Yet, the role of sGC in age- and sex-dependent RGC function remains uncharacterized. We investigated how preventing NO binding to sGC influences RGC function in the context of aging and sex by combining bulk and single-cell RNA sequencing, Western blotting, mitochondrial ultrastructural analysis, visual acuity measurements, and in vivo measurements of retinal oxidative metabolism. We found that global sGCα1 deletion impairs visual function and RGC health in aging female mice, while male mice remained unaffected. Glucose uptake was significantly disrupted in female sGCα1(-/-)retinas with age, and accompanied by reduced retinal expression of the glucose transporter, GLUT1. Aged sGCα1(-/-) females also exhibited dysregulated retinal mitochondrial gene and protein expression and increased nitrosative stress localized to the RGC layer. RGC mitochondria in male mice increased in size with age, while female mitochondria did not. Furthermore, retinal metabolic analysis showed decreased oxygen consumption rate in aged female but not male sGCα1(-/-)retinas, suggesting impaired oxidative metabolism. These findings reveal a potential sex-specific role for cGMP signaling in maintaining retinal metabolic integrity and RGC function with age. Our results point to a possible mechanistic link between impaired cGMP signaling and age-related retinal neurodegeneration in females, highlighting the sGC-cGMP signaling pathway as a promising therapeutic target for glaucoma and other CNS neurodegenerative diseases.