Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse

Abstract

The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788 ± 16% (SD), which dropped to 49,545 ± 20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p < 0.05) on Chromosome 18 between 53.6 and 57 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.

Identification of lncRNAs Associated with the Pathogenesis of Diabetic Retinopathy: From Sequencing Analysis to Validation via In Vivo and In Vitro Experiments

“…ALDH enzymes also play important roles in embryogenesis and development, neuronal transmission, oxidative stress, and cancer [ 27 ]. Raldh3 knockout inhibits the synthesis of retinol and causes deformities of eyes and noses [ 28 ], and ALDH7A1 is associated with the butyrate pathway related to glaucoma risk [ 29 ]. ALDH3a1 level is high in the cornea and lens, regulating corneal epithelial differentiation, maintaining corneal epithelial homeostasis, and protecting eyes from cataracts through both nonenzymatic and enzymatic functions [ 30 , 31 ].…”

Evaluation of Redox Profiles of the Serum and Aqueous Humor in Patients with Primary Open-Angle Glaucoma and Exfoliation Glaucoma

“…The excess production of reactive oxygen species, such as superoxide, can damage a wide variety of biomolecules and induce cellular dysfunction [ 20 ], including trabecular meshwork cells. The trabecular dysfunction can obstruct the outflow of the aqueous humor (AH) [ 17 , 18 ], leading to IOP elevation and consequently contributing to retinal ganglion cell death [ 21 ]. In contrast, antioxidants can scavenge reactive oxygen and nitrogen species by interacting with various redox signaling pathways [ 22 ], which prevents retinal ganglion cell death [ 23 ].…”

CircXPO5 Plays a Neuroprotective Function in the Lateral Geniculate Nucleus of Glaucoma by Regulating GRIN2A

“…With the increase in IOP, the interruption of the retrograde transmission of neurotrophic factors in the optic nerve axon of the optic nerve head is considered the main mechanism of RGC death [ 29 ], highlighting the need to protect RGCs from damage [ 30 , 31 ], or replace them with stem cell-derived counterparts [ 32 , 33 ]. In recent years, studies have found degeneration and atrophy of the visual center of glaucoma [ 8 , 33 ].…”