The retina is a structure of the eye that converts the light signal into a chemical signal that is then conveyed to the brain for being interpreted. The retina is a complex structure made of different cell types, carefully organized in layers. Photoreceptors are the cells responsible to capture the light and are divided in two sub-categories: cones and rods. The rods are responsible for night vision, as they respond to dim light, while the cones are responsible for color vision.
Several eye diseases affect photoreceptors.
Retinitis Pigmentosa (RP) is a progressive disease leading to neurodegeneration of photoreceptors. It is the most common form of inherited degenerative retinal disease. Firstly, rods die causing patients to lose their night vision, and only afterwards, cones die. With cones degeneration, patients lose also daylight-vision, becoming progressively completely blind.
A promising treatment for RP involves the Rod Derived Cone Viability Factor, RdCVF. RdCVF is secreted from rods and binds to a receptor that is expressed on cones surface. RdCVF receptor is called Basigin-1.
In vivo cone cells usually start degenerating after seven days, but cell survival is increased when RdCVF is added to the culture medium. On the other hand, when the expression of the receptor Basigin-1 on cones surface is knocked down (see “Methods” section of this website for details on knock down technique), the treatment with RdCVF does not affect cones survival. The lack of protection lead the cells to die after seven days in culture.
Why? How does RDCVF work? What happens after RDCVF binds to Basigin-1 receptor?
Basigin-1 binds to GLUT1. GLUT1 is a glucose transporter, a protein inserted in the cell membrane mediating the uptake of glucose inside cones cells. The formation of a complex Basigin-1/RdCVF/GLUT1 at the cell surface of cones stimulates glucose uptake that is therefore faster than in resting conditions.
The increased survival is due to the increased glucose uptake in the cells expressing Basigin-1 after RDCVF binding. Once taken up by the cells, glucose is metabolized into a molecule called pyruvate that is successively transformed into lactate. This process is called aerobic glycolysis.
Lactate has a known role in cell protection in retina. Indeed, mis-functioning and consequent degeneration of photoreceptors and other retinal cells can be ameliorated by lactate. In case of glucose deprivation, cells can use lactate to produce energy.
When Basigin-1 is silenced (= knocked down), RdCVF-induced uptake of glucose is slowed down, as well as lactate production, preventing cell protection.
And in vivo?
When RdCVF is expressed in mouse models undergoing rods and cones degeneration, cones survival increased; and in a rat model of RP, cones functionality is preserved when RdCVF is expressed.
What about the patients?
As RdCVF receptors are still present at the cell surface of the surviving cones in RP retinas, RdCVF administration could protect cones and increase their survival in RP patients, preserving, at least partly, their vision.
However, controlling glucose metabolism can be also useful to modulate other cell processes. Indeed, normally photoreceptors replace periodically their outer segment, which is lost and digested by retinal pigmented epithelial cells (RPE, cells located right next to photoreceptors layer that have a trophic and protective role). In order to do so, lipids proteins and other membrane components have to be produced, and that requires glucose-derived energy. By boosting glucose uptake and metabolism, RdCVF might be used in this process to provide the high energy demanded for renewing the outer segment of photoreceptors. Outer segments of photoreceptors are indeed longer in RdCVF-treated animals, and this might be because a part of the glucose produced by RdCVF stimulation is not converted into lactate, but used for making outer photoreceptors parts.
Reference: Najate Ait-Ali et al., Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis. Cell 2015.