A discovery in French-speaking Switzerland could cure a serious eye disease

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By understanding a mechanism causing a condition that can lead to blindness, researchers from Geneva and Lausanne are giving 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 Hospital

Retinitis pigmentosa is the most common inherited retinal disease in humans, affecting one in 4,000 worldwide. The onset of the first symptoms generally occurs between the ages of 10 and 20 with loss of night vision. Subsequently, the visual field narrows into “tunnel vision” and eventually leads to blindness around the age of 40.

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

Mutation of four proteins

Mutations in the genes of four proteins located at the level of this connector cilia are all associated with retinal pathologies presenting degeneration of photoreceptors. These four proteins had been identified by the laboratory of Paul Guichard and Virginie Hamel of the Department of Molecular and Cellular Biology of the Faculty of Sciences of the University of Geneva (UNIGE). He had located them at the level of the centrioles, cylindrical structures formed of microtubules and present in all animal cells. “In the centriole, these proteins hold the different microtubules together by acting like a zipper. We wondered if they did not play the same role in the tubular structures of the connector eyelashes”, explains Virginie Hamel, last author of the study which appears this June 16 in the journal 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 tissues with a resolution hitherto never achieved. The biologists focused on the structure of connector cilia from mice and which presented (or not) a mutation in the gene of one of the four proteins mentioned. These observations were made at different life stages.

“In the absence of the mutation, we found that these proteins provide, just as we had previously seen in centrioles, cohesion between microtubules by forming a zipper that closes as development progresses” , explains Olivier Mercey, researcher in the Department of Molecular and Cellular Biology and first author of the study.

On the other hand, when the gene for this protein is mutated, although the structure of the microtubules appears normal in the first days, they gradually become less and less attached to each other. In adulthood, the affected mice eventually exhibit microtubules that are no longer “zipped” to each other and eventually collapse, leading to photoreceptor cell death.

Attempt to restore the “molecular zip”

This work, supported by the European Research Council (ERC) and the Pro Visu Foundation, has led to a better understanding at the molecular and structural level of retinitis pigmentosa which makes it possible to envisage therapeutic treatments acting before cell degeneration. “By injecting the protein in patients suffering from certain retinitis pigmentosa, it can be assumed that the molecular zip can be restored to guarantee the structural integrity of the microtubules of the connecting cilia, thus avoiding the death of the photoreceptor cells. 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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