Most monogenic forms of inherited retinopathies are associated with genes expressed in photoreceptors (PR) or retinal pigment epithelium (RPE) where they encode proteins that are critical for PR structure, function and survival. Specific cellular processes and biochemical pathways implicated in retinal dystrophies include: PR development, morphogenesis, photo transduction, visual cycle, cellular metabolism, protein folding, among others. The vision and survival of rod and cone require continuous renewal of the visual chromophore, the 11-cis retinal, which forms together with the opsin proteins, the rhodopsin and cone visual pigments.
11-cis retinal is produced from vitamin A, an all-trans retinol, which is supplied with provitamin carotene from diet. In the outer segment (OS) discs of PR, light cause photoisomerization of 11-cis-retinal to all-trans-retinal, this is then reduced to all-trans retinol. Renewal of 11-cis retinal is provided by the visual cycle, an enzymatic pathway which involves the adjacent RPE and Müller cells. Stargardt pathophysiology involves rapid accumulation of toxic bisretinoid by-products such as A2E in the RPE.
1- Lipid metabolism is of major importance for retina integrity and its deregulation can lead to pigmentary retinopathies. Lipid disorders have been implicated in macular degeneration such as the age-related macular degeneration (AMD) and Stargardt disease. Loss of function of fatp gene, the orthologue of FATP1 in drosophila, leads to PR death (Dourlen, P et al., PLoS genetics 2012). We propose to study the conserved functions of Fatp genes in drosophila and mice and the mechanisms by which lipid deregulations lead to perturbation of PR function and survival.
2- The carbonyl and oxidative stress (COS) play a substantial role in Stargardt disease as well as in aging pathologies like age-related macular degeneration (AMD). We will develop chemicals that should be efficient as anti-COS: first, to slow down the formation of bis-retinoid derivatives, such as A2E, by quenching excess of all-trans-retinal in the photoreceptor cells, second, to quench oxidant stressors avoiding damages related to oxidation of A2E in the RPE.Strength of our expertise in the biochemistry of the retina and the visual cycle, we will work on post-genomic projects for studying new gene mutations and analyzing phenotype of new animal models for gene therapy. These post-genomics will be further extended to new genes identified by genetic analysis for perse retinal dystrophies.
Biochemistry and molecular biology, yeast two-hydrid screening, recombinant protein interaction, cell cultures, cell death and cell survival measurements, HLPC analysis of retinoids, analytical chemistry to probe the visual cycle, physiology of the visual function in mice.
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- Bertrand Mollereau (Equipe Apoptose et Neurogénétique, ENS de Lyon).
- David Cia (UMR Inserm 1107, Laboratoire de Biophysique Neurosensorielle, Facultés de Médecine et de Pharmacie, Clermont-Ferrand).
- Céline Crauste, Joseph Vercauteren et Thierry Durand, Institute of Biomolecules Max Mousseron (IBMM), UMR5247-CNRS-UM1-UM2-ENSCM, Faculty of Pharmacy, Montpellier.
- Peter Humphries, Ocular Genetics Unit, Department of Genetics, Trinity College Dublin, Dublin, Ireland.