A discovery in western Switzerland could cure a serious eye disease

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By understanding a mechanism that causes a condition that can lead to blindness, researchers from Geneva and Lausanne offer hope for a therapy.

The disease begins with a loss of night vision, then a narrowed field of vision, and leads to blindness around the age of 40.

Jules Gonin Eye Clinic

Retinitis pigmentosa is the most common inherited retinal disease in humans, affecting one in 4,000 people worldwide. The first symptoms usually appear between the ages of 10 and 20 with loss of night vision. The field of vision then narrows to “tunnel vision” and finally leads to blindness around the age of 40.

This disease is characterized by a degeneration of light-sensitive cells called photoreceptors. These specialized nerve cells in the retina are responsible for converting light into nerve signals. A cilium connects the light-sensitive pigments found on the cell’s outer segment to the internal metabolic machinery that powers the cell.

mutation of four proteins

Mutations in the genes of four proteins located at the level of these connecting cilia are all associated with retinal pathologies representing photoreceptor degeneration. These four proteins were identified by the laboratory of Paul Guichard and Virginie Hamel from the Department of Molecular and Cellular Biology of the Faculty of Science at the University of Geneva (UNIGE). He located them at the level of the centrioles, cylindrical structures made of microtubules that are found in all animal cells. “In the centriole, these proteins hold the different microtubules together by acting like a zipper. We wondered if they didn’t play the same role in the tubular structures of the connecting cilia,” explains Virginie Hamel, senior author of the study, which appears in the journal on June 16 PLOS biology.

Thanks to expansion microscopy techniques, which make it possible to inflate the cells without deforming them, the scientists were able to observe the retinal tissue with an unprecedented resolution. The biologists focused on the structure of connecting cilia from mice that had (or did not) have a mutation in the gene of one of the four proteins mentioned. These observations were made at different life stages.

“Without the mutation, we found that, just as we had previously seen in centrioles, these proteins provide cohesion between microtubules by forming a zipper that closes as development progresses,” explains Olivier Mercey, researcher in the department for Molecular and Cellular Biology and first author of the study.

On the other hand, if the gene for this protein is mutated, the structure of the microtubules may appear normal for the first few days, but they gradually become less and less attached to each other. Eventually, in adulthood, affected mice exhibit microtubules that are no longer “zipped” together and eventually collapse, leading to the death of the photoreceptor cells.

Attempt to restore the “molecular zipper”.

This work, supported by the European Research Council (ERC) and the Pro Visu Foundation, has led to a better understanding of retinitis pigmentosa at a molecular and structural level, making it possible to envisage therapeutic treatments that act before cellular degeneration. “By injecting the protein into patients suffering from a specific retinitis pigmentosa, it can be expected that the molecular zipper can be restored to ensure the structural integrity of the microtubules of the connecting cilia, thus avoiding photoreceptor cell death. We are evaluating this approach in collaboration with our colleagues from the University of Lausanne (UNIL) and the Jules-Gonin Ophthalmic Hospital, Yvan Arsenijevic and Corinne Kostic,” concludes Paul Guichard, co-last author of the study.

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