Scientists identified a molecular mechanism that causes blindness

New hope for therapy against retinitis pigmentosa.


Retinitis pigmentosa is a degenerative eye disease characterized by progressive vision loss, usually leading to blindness. Inherited retinal degeneration due to the loss of photoreceptor cells is a leading cause of human blindness. While structural defects of the photoreceptor cells associated with retinal degeneration have been observed, the molecular mechanisms involved are not understood.

Scientists from the University of Geneva (UNIGE), in collaboration with the University of Lausanne (UNIL), have identified a molecular mechanism that causes degeneration of the eye’s photoreceptors, which can lead to blindness. They identified the essential role played by a molecular zipper formed by four proteins. The absence of this zipper leads to cell death in retinal cells.

The retina’s specialized neuronal cells are responsible for converting light into nerve signals. The light-sensitive pigments are positioned on stacks of discs that make up the cell’s outer segment. The connecting cilium connects the inner and outer segments, containing all the metabolic machinery required for cell operation.

Mutations in the genes of four proteins located in this connecting cilium are all associated with retinal pathologies presenting degeneration of photoreceptors. Scientists identified these proteins, which are located in centrioles, cylindrical structures made of microtubules and present in all animal cells.

Virginie Hamel, the last author of the study, said, “In the centriole, these proteins ensure the cohesion of the different microtubules by acting like a zipper. We wondered if they did not play the same role in the tubular structures of the connecting cilium.”

Using this, the scientists could observe retinal tissue with a resolution never achieved. The biologists focused on the structure of connecting cilia from mice that had – or did not have – a mutation in the gene for one of the four mentioned proteins. These observations were conducted at different life stages.

Olivier Mercey, a researcher in the Department of Molecular and Cellular Biology and the first author of the study, said, “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.”

When the gene for this protein is mutated, however, the structure of the microtubules initially appears normal, but the microtubules gradually become less and less connected to each other. In adulthood, the affected mice’s microtubules are no longer “zipped” together and finally collapse, resulting in photoreceptor cell loss.

Concludes Paul Guichard, coauthor of the study, said“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.”

The study has led to a better understanding of the molecular and structural level of retinitis pigmentosa, which allows us to consider treatments that act upstream of cell degeneration.

Journal Reference:

  1. Olivier Mercey, Corinne Kostic, et al. The connecting cilium inner scaffold provides a structural foundation that protects against retinal degeneration. DOI: 10.1371/journal.pbio.3001649
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