Pathological blindness: why exactly do photoreceptors die?

Schweizerischer Nationalfonds / Swiss National Fund

Bern (ots)

Retinitis pigmentosa, a common eye disease, causes a slow loss of retinal rods and cones. The analysis of certain cells gives an insight into the genesis of this process.

Night blindness and tunnel vision, then a loss of contrast and color, which in the worst cases leads to complete blindness: This is the typical course of retinitis pigmentosa. This hereditary disease of the retina affects around 1 in 3000 people in Switzerland. In these patients, the rods responsible for black and white vision begin to deteriorate, followed by the cones, which allow color vision.

“We know very well the evolution of degeneration in advanced stages. On the other hand, the molecular mechanisms underlying the disease remain a mystery,” explains Christian Grimm, Head of the Laboratory for Retinal Cell Biology at the University of Zurich. As part of a study funded by the SNSF, his research team carried out analyzes using innovative techniques that uncovered the active genes in the photoreceptors at the very beginning of the degenerative process. The purpose of this study? Find a treatment that prevents retinal degeneration.

The researchers used mice for this. Indeed, due to a congenital genetic abnormality, they develop retinitis pigmentosa with a development identical to human pathology. Almost 20,000 rods and cones have been isolated from mouse retinas. The scientists then determined the degeneration phase of each photoreceptor and which genetic messages were already being read at this point in time. This method provides information about the type and amount of proteins produced by the cell. Thanks to comparisons of healthy and diseased photoreceptors, more than 200 proteins have been identified, which are mainly produced in the early stages of the disease.

Is the gene an ally or an enemy?

The scientists noticed that a gene called EGR1, which contains the message for the EGR1 protein, is read particularly frequently in the rods at the beginning of the degenerative process. This protein is known to control the activity of many other genes. Shortly before the cell dies, the gene is no longer read in the rods but in the cones, which in turn die off.

The research team therefore assumes that the EGR1 protein plays a significant role in the degenerative process. “But we don’t know whether the protein is trying to help the photoreceptors survive or whether it is accelerating the degeneration,” explains Christian Grimm. This question is the subject of a follow-up project in which the EGR1 gene is deactivated on the one hand and hyperactivated on the other. At best, the results of this project form a starting point for the development of a new therapy.

Although new-generation gene therapies have successfully treated inherited eye diseases, including a specific form of retinitis pigmentosa, in recent years, the problem remains unsolved. “There are more than 250 mutations responsible for blindness. Developing a gene therapy for each of them would be far too expensive,” explains Christian Grimm. “That’s why we are working to develop a suitable treatment for different forms of blindness.”

Karademir et al.: Single-cell RNA sequencing of the retina in a model of retinitis pigmentosa reveals early responses to degeneration in rods and cones. BMC Biology (2022): https://doi.org/10.1186/s12915-022-01280-9D

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The text of this notification and further information are available on the website of the Swiss National Science Foundation.

Contact:

Christian Grimm, Laboratory of Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Wagistrasse 14, 8952 Schlieren, Tel: +41 43 253 30 01, email: cgrimm@opht.uzh .ch

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