RESUMO
Visual perception by photoreceptors relies on the interaction of incident photons from light with a derivative of vitamin A that is covalently linked to an opsin molecule located in a special subcellular structure, the photoreceptor outer segment. The photochemical reaction produced by the photon is optimal when the opsin molecule, a seven-transmembrane protein, is embedded in a lipid bilayer of optimal fluidity. This is achieved in vertebrate photoreceptors by a high proportion of lipids made with polyunsaturated fatty acids, which have the detrimental property of being oxidized and damaged by light. Photoreceptors cannot divide, but regenerate their outer segments. This is an enormous energetic challenge that explains why photoreceptors metabolize glucose through aerobic glycolysis, as cancer cells do. Uptaken glucose produces metabolites to renew that outer segment as well as reducing power through the pentose phosphate pathway to protect photoreceptors against oxidative damage.
Assuntos
Glucose/metabolismo , Via de Pentose Fosfato , Células Fotorreceptoras/metabolismo , Retina/metabolismo , Doenças Retinianas/metabolismo , Transdução de Sinais , Animais , Ácidos Graxos/metabolismo , Humanos , Oxirredução , Estresse Oxidativo , Células Fotorreceptoras/citologia , Rodopsina/metabolismoRESUMO
Retinal degenerative diseases are a major cause of untreatable blindness due to a loss of photoreceptors. Recent advances in genetics and gene therapy for inherited retinal dystrophies (IRDs) showed that therapeutic gene transfer holds a great promise for vision restoration in people with currently incurable blinding diseases. Due to the huge genetic heterogeneity of IRDs that represents a major obstacle for gene therapy development, alternative therapeutic approaches are needed. This review focuses on the rescue of cone function as a therapeutic option for maintaining central vision in rod-cone dystrophies. It highlights recent developments in better understanding the mechanisms of action of the trophic factor RdCVF and its potential as a sight-saving therapeutic strategy.
Assuntos
Distrofias de Cones e Bastonetes/terapia , Terapia Genética , Vetores Genéticos/uso terapêutico , Células Fotorreceptoras Retinianas Cones/fisiologia , Tiorredoxinas/fisiologia , Processamento Alternativo , Sequência de Aminoácidos , Comunicação Celular , Dependovirus/genética , Proteínas do Olho/fisiologia , Heterogeneidade Genética , Glicólise , Humanos , Modelos Moleculares , Medicina de Precisão , Conformação Proteica , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Tiorredoxinas/química , Tiorredoxinas/genética , Tiorredoxinas/uso terapêutico , Pesquisa Translacional Biomédica , Resultado do TratamentoRESUMO
The nucleoredoxin-like gene Nxnl1 (Txnl6) and its paralogue Nxnl2 encode the rod-derived cone viability factors (RdCVF and RdCVF2), which increase the resistance to photooxidative damage and have therapeutic potential for the survival of cones in retinitis pigmentosa. In this study, the transcription of Nxnl genes was investigated as a function of the day/night cycle in rats. The transcript levels of Nxnl1 and Nxnl2 were seen to display daily rhythms with steadily increasing values during the light phase and peak expression around dark onset in preparations of whole retina, photoreceptor cells and-but only in regard to Nxnl1-in photoreceptor-related pinealocytes. The cycling of Nxnl1 but not that of Nxnl2 persisted in constant darkness in the retina. This suggests that daily regulation of Nxnl1 is driven by a circadian clock, whereas that of Nxnl2 is promoted by environmental light. The present data indicate clock- and light-dependent regulations of nucleoredoxin-like genes that may be part of a protective shield against photooxidative damage.
Assuntos
Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica/fisiologia , Proteínas Nucleares/metabolismo , Oxirredutases/metabolismo , Glândula Pineal/metabolismo , RNA Mensageiro/metabolismo , Retina/metabolismo , Animais , Escuridão , Feminino , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Microdissecção e Captura a Laser , Masculino , Proteínas Nucleares/genética , Oxirredutases/genética , Células Fotorreceptoras/metabolismo , Glândula Pineal/citologia , Ratos , Ratos Sprague-Dawley , Retina/citologiaRESUMO
The most common hereditary retinal degeneration, retinitis pigmentosa (RP), leads to blindness by degeneration of cone photoreceptors. Meanwhile, genetic studies have shown that a significant proportion of RP genes is expressed only by rods, which raises the question of the mechanism leading to the degeneration of cones. Following the concept of sustainability factor cones, rods secrete survival factors that are necessary to maintain the cones, named Rod-derived Cone Viability Factors (RdCVFs). In patients suffering from RP, loss of rods results in the loss of RdCVFs expression and followed by cone degeneration. We have identified the bifunctional genes nucleoredoxin-like 1 and 2 that encode for, by differential splicing, a thioredoxin enzyme and a cone survival factor, respectively RdCVF and RdCVF2. The administration of these survival factors would maintain cones and central vision in most patients suffering from RP.