RODCELL

Cellular and molecular mechanisms of the light response in photoreceptor cells of the mammalian retina

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 Obiettivo del progetto (Objective)

'Genetic defects in proteins involved in the transduction of light in photoreceptor cells of the retina lead to severe retinal degenerations and blindness. Mutations that primarily affect rod function lead to retinitis pigmentosas. These diseases affect 1 in 4000 individuals, initially causing night blindness. As the gradual loss of rods eventually compromises cone cell viability, they lead to blindness. Mutations that affect cone function lead to cone dystrophies (CDs) or macular degenerations. There is no current cure for these diseases. The applicant will establish a lab in which the main interests will be: 1) study intracellular signaling in rod and cone photoreceptor cells in response to light, by combining mouse genetics with morphological, biochemical and electrophysiological analysis; and 2) use mouse models to study how genetic defects in these signaling pathways lead to retinal degeneration. In this frame, the first main aim of this proposal is to establish mouse models of the adCDs caused by mutations in the gene encoding Guanylate Cyclase Activating Protein 1 (GCAP1), a Ca2-binding protein that regulates cGMP synthesis in rods and cones. By expressing mutant forms of the protein in murine rods, and subsequently in cones we will study the pathways leading to cell death in vivo. The second main aim is to study the mechanisms that govern arrestin intracellular localization in darkness and its massive redistribution in response to light. This is a defense mechanism of rod photoreceptors to adapt and to protect themselves to prolonged light exposures (e.g. during cone-operated vision), and its understanding will be relevant for the dark/light physiology or photoreceptor cells.'

Descrizione progetto (Article)

A team of scientists working under the EU-funded project 'Cellular and molecular mechanisms of the light response in photoreceptor cells of the mammalian retina' (Rodcell) is working to discover intracellular signalling events taking place in rod and cone photoreceptor cells, and uses a mouse model to study how genetic flaws lead to retinal degeneration.

The primary aim is to describe what happens in the photoreceptor cells of the mammalian retina in response to light. This will help characterise their relevance for cell function and viability. Researchers are combining mouse genetics with morphological, biochemical and electrophysiological analysis. They have already generated a mouse model that will represent a sub-group of mutations in the relevant genes. And the project partners believe this could be a prototype for a wider range of retinal disorders caused by autosomal dominant mutations.

This means that the gene carrying a mutation is located on one of the autosomes - chromosome pairs 1 through 22. In terms of inheritance, 'dominant' means that having a mutation in just one of the two copies of a particular gene is all it takes for a person to have a trait, such as the retinal disorder.

Initial results indicate that harmful genes and mutations lead to toxicity by affecting the ability of the protein to be properly delivered to the rod outer segment. The protein is not allowed to 'fold' properly and so its accumulation is likely to be responsible for causing proteotoxicity and a stress response leading to cell death. The Rodcell project is now working to characterise the 'stress response' in this transgenic pathway.