New discovery may result in the event of therapeutic approaches for retinitis pigmentosa
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Retinitis pigmentosa, a degenerative genetic illness of the attention, is characterised by progressive imaginative and prescient loss, often resulting in blindness. In some sufferers, structural defects within the photoreceptor cells have been noticed, however the molecular mechanisms concerned are usually not understood. A workforce from the University of Geneva (UNIGE), in collaboration with the University of Lausanne (UNIL), has recognized the important position performed by a molecular zipper fashioned by 4 proteins. The absence of this zipper results in cell dying in retinal cells. This discovery may result in the event of therapeutic approaches for retinitis pigmentosa. This work may be learn within the journal PLOS Biology.

Retinitis pigmentosa is the most typical hereditary retinal illness in people, with a prevalence of 1 in each 4,000 folks worldwide. The first signs often seem between the ages of 10 and 20 with a lack of evening imaginative and prescient. Thereafter, the visible area narrows right into a “tunnel vision” to lastly result in blindness across the age of 40. This illness is characterised by a degeneration of the light-sensitive cells, the photoreceptors.

These specialised neuronal cells of the retina are accountable for the conversion of sunshine right into a nerve sign. The outer section of the cell is made up of stacks of discs on which the light-sensitive pigments are positioned. The interior section comprises all of the metabolic equipment important to the functioning of the cell and is linked to the outer section by the connecting cilium.

A molecular zipper

Mutations within the genes of 4 proteins positioned on this connecting cilium are all related to retinal pathologies presenting degeneration of photoreceptors. These 4 proteins had been recognized by the laboratory of Paul Guichard and Virginie Hamel of the Department of Molecular and Cellular Biology of the Faculty of Science. They are positioned in centrioles, cylindrical buildings product of microtubules and current in all animal cells.

In the centriole, these proteins make sure the cohesion of the totally different microtubules by performing like a zipper. We puzzled if they didn’t play the identical position within the tubular buildings of the connecting cilium.”

Virginie Hamel, final writer of the research

Observations with unprecedented precision

Thanks to an growth microscopy method optimized by the group of Virginie Hamel and Paul Guichard, which permit cells to be inflated with out deforming them, the scientists have been in a position to observe retinal tissue with a decision by no means achieved. The biologists centered on the construction of connecting cilia from mice that had – or didn’t have – a mutation within the gene for one of many 4 talked about proteins. These observations have been carried out at totally different life levels. “In the absence of the mutation, we found that these proteins ensure, just as we had previously seen in centrioles, the cohesion between microtubules by forming a zipper that closes as development proceeds,” explains Olivier Mercey, researcher within the Department of Molecular and Cellular Biology and first writer of the research.

On the opposite hand, when the gene for this protein is mutated, though the construction of the microtubules seems regular within the first days, the microtubules step by step grow to be much less and fewer connected to one another. In maturity, the affected mice have microtubules which are now not “zipped” collectively in any respect and ultimately collapse, resulting in cell dying of the photoreceptors.

Restoring the “molecular zipper” to stop cell dying

This work, supported by the European Research Council (ERC) and the Pro Visu Foundation, has led to a greater understanding on the molecular and structural stage of retinitis pigmentosa, which permits to think about therapeutic therapies that act upstream of cell degeneration.

“By injecting the protein into patients suffering from certain types of retinitis pigmentosa, we can imagine that the molecular zipper could be restored to ensure the structural integrity of the microtubules of the connecting cilia, thus preventing the death of photoreceptor cells. We are evaluating this approach in collaboration with our colleagues from UNIL and the Jules-Gonin Ophthalmic Hospital, Yvan Arsenijevic and Corinne Kostic”, concludes Paul Guichard, coauthor of the research.


Journal reference:

Mercey, O., et al. (2022) The connecting cilium interior scaffold supplies a structural basis that protects in opposition to retinal degeneration. PLOS Biology.

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