Cone dystrophies and retinal degeneration from protein structures to biological networks. Toward the design of therapeutic molecules

Cone dystrophy (COD) is a severe form of retinal disorder affecting photoreceptors, the cells where the visual signal originates. COD leads to decreased central and colour vision, photophobia. In several patients with COD cone dysfunction the disease is often followed by the degeneration of rods, another type of photoreceptor. As a consequence, the evolution of the disease may result also in the progressive loss in peripheral vision. Currently, no cure exists for these diseases, which affect 1 in 10,000 people. In the last years an increasing number of genetic mutations have been identified in the gene responsible for the production of GCAP1, a sensor protein detecting intracellular calcium and regulating important biological processes. The consequence of alterations in GCAP1 have been only partly explored and mechanisms leading to the onset of the disease remain largely unclear. In this project, we will characterize GCAP1 variants associated with COD by applying experimental approaches and computer simulations. We will compare structural and functional properties in normal and disease-associated forms of GCAP1 and unveil the alterations in the interaction with the guanylate cyclase, an enzyme fundamental for keeping regular calcium levels and avoiding cell death. This information will be used to identify novel molecules capable of dampening and possibly eliminating the mis-regulation induced by altered GCAP1. We will also test the therapeutic potential of the newly identified molecules by making use of a suitable animal model of disease.