The results suggest that the ligand is required during cone opsin synthesis for successful opsin trafficking and that without 11-cis retinal, cones may degenerate because of opsin mislocalization. These results may have important consequences for the treatment of cone dystrophies.
In the Rpe65(-/-) mouse, the expression of cone-specific genes is downregulated and is accompanied by cone degeneration at early ages. Early administration of 9- or 11-cis retinal can partially prevent cone loss, suggesting that the absence of 11-cis chromophore may be responsible for the early cone degeneration.
In the rd/rd mouse, photoreceptor degeneration is due to a mutation of the rod-specific enzyme cGMP phosphodiesterase, resulting in permanently opened cGMPgated cation channels in the rod outer segment membrane that allow Na ؉ and Ca 2؉ ions to enter the cell, resulting in possibly toxic levels of Ca 2؉ . To identify pathways involved in cell death of the rd/rd rods, we evaluated gene expression in the rd/rd and wild type (wt) mouse retina (U74A oligonucleotide arrays (Affymetrix)) over the known time course of photoreceptor degeneration. 181 genes passed the selection criteria (low standard deviation and high correlation between replicates), falling into six clusters. For any given pair of genes, an expression profile correlation distance and a semantic distance (one for each class of gene ontology terms) were established using newly designed software. Gene expression in rd/rd started to deviate from wt by postnatal day 10. The reduction in photoreceptorspecific genes followed the known time course of photoreceptor degeneration. Likewise the increase in transcription factors and apoptosis-and neuroinflammation-specific genes followed the kinetics of the rise in intracellular cGMP in the rod photoreceptors. In addition, genes coding for calcium-binding proteins and those implicated in tissue and vessel remodeling were increased. These results suggest that photoreceptor degeneration in the rd/rd mouse is a process starting with Ca 2؉ toxicity followed by secondary insults involving multidestructive pathways such as apoptosis and neuroinflammation, presumably boosting morphological changes. All of these components need to be addressed if rods are to be successfully protected.Photoreceptors are very stable but at the same time extremely fragile cells (1). Photoreceptor degeneration can be caused by any changes that alter the composition of the signal transduction cascade, influence the energy metabolism or the oxygen tension in the outer retina, or disturb the phagocytic process by the retinal pigment epithelium. In the rd/rd mouse, photoreceptor degeneration is due to an autosomal recessive mutation of the enzyme cGMP phosphodiesterase, which is an important component in the phototransduction cascade (2). The genetic defect is due to the integration of a provirus (Xmv-28) into intron I of the  subunit of the enzyme and subsequent incorrect splicing (3). Degeneration starts at about P8, 1 which is the time point at which naturally occurring cell death starts in the wild type mouse (4), and commences very quickly.The resulting lack in cGMP phosphodiesterase activity causes a dramatic increase in cytoplasmic cGMP concentration (5). This in turn results in permanent opening of the cGMPgated cation channels in the photoreceptor membrane, allowing the excessive entry of extracellular ions, particularly calcium. It has been suggested that this increase in intracellular calcium causes a metabolic overload of the cells, eventually leading to cell death by apoptosis (6). Likewise it has been suggested that either disruptio...
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