Modulation of Aerobic Glycolysis Genes During the Progression of Retinitis Pigmentosa

Photoreceptors are retinal cells with a high glucose metabolism and retinal degeneration, specifically retinitis pigmentosa (RP), affects glycolysis. We aimed to evaluate changes in the expression of genes related to glucose metabolism in rod photoreceptors at different stages of retinal degeneration in murine models and human retinal organoids.

RNA sequencing (RNA-seq) analysis was performed on a photoreceptor-like cell line induced to undergo degeneration and validated by real-time qPCR analysis of retinas from two murine models and one human organoid model of RP. Bioinformatic analysis was performed on published RNA-seq datasets from three murine RP models. Real-time qPCR analysis was also performed on retinas treated with an adeno-associated virus type 2 vector carrying the neurotrophic H105A peptide, derived from the pigment epithelium-derived factor.

The aerobic glycolysis genes, Hk2, Pkm1, Pkm2, Ldha, and Slc6a6 and other glucose metabolism genes were found downregulated in the in vitro model of photoreceptor degeneration and in the in vivo RhoP23H/+, rd1, and rd10 models at early stages of the disease. The decreased expression of the aerobic glycolysis genes, except for PKM2, was confirmed in human organoids with mutations in the USH2A gene associated with RP. Expression was partially recovered in RhoP23H/+ retinas after treatment with the adeno-associated virus type 2 vector expressing the neurotrophic H105A peptide.

Glucose metabolism gene expression was found altered during the progression of RP in murine and human models of the disease. Expression was partially recovered in a molecular response to the treatment with the neurotrophic factor H105A.