What triggers photoreceptor cell death in a disease leading to blindness?

In the common eye disease retinitis pigmentosa, the rods and cones of the retina slowly die. Single cell analysis provides insights into the onset of this process.

First night blindness and tunnel vision, then the loss of contrast and colour and, in the worst case, total blindness: this is the typical course of retinitis pigmentosa, a hereditary disease of the retina that affects about one in 3000 people in Switzerland. The rods responsible for light and dark adaptation in their retinas atrophy first, followed by the cones that enable colour vision.

"How degeneration occurs in the later stages is very well known. But we don't yet know the triggering molecular mechanisms," says Christian Grimm, head of the Lab for Retinal Cell Biology at the University of Zurich. An SNSF-funded study by his research group has now used an innovative technique to analyse which genes are active in the photoreceptors at the very beginning of the degenerative process. The goal: to find a treatment that will save the retina from decay.

For their study, the researchers used mice that develop retinitis pigmentosa due to a natural genetic defect that is similar to the human disease. They isolated almost 20,000 rod and cone cells from the retinas of these animals. For each of these photoreceptors, they then determined which phase of degeneration it was in, and which genetic blueprints were being read at that time – this method allows conclusions to be drawn about which types of proteins a cell is currently producing and in what quantities. By comparing healthy photoreceptor cells with those that are already diseased, they were able to identify more than 200 proteins that are produced mainly in the early stages of the disease.

Does the gene help or destroy?

At the start of the degenerative process, a gene called EGR1, which contains the blueprint for the protein EGR1, was particularly frequently detected in the rods. This protein is known to control the activity of many other genes. Shortly before cell death, the gene is no longer found in the rods, but in the cones, whereupon these also begin to die.

For this reason, the research team suspects that the EGR-1 protein plays a key role in the process of degeneration. "However, we don't know if the protein is trying to help the photoreceptors survive, or if it is accelerating their death," Grimm said. This will now be clarified by a follow-up project in which the EGR1 gene is switched off once and overactivated once. Researchers hope to be able to use the findings as a starting point for the development of new treatments.

In recent years, novel gene therapies have been used to successfully treat many hereditary eye diseases, including a specific form of retinitis pigmentosa – but the problem is far from solved. "There are more than 250 different mutations that cause blindness, and developing gene therapy for all of them would be far too expensive," Grimm says. "So now we're trying to find something that can fundamentally help against different forms of blindness."