Since blindness in patients suffering from retinitis pigmentosa is caused by non-cell autonomous degeneration of cones that results from cell autonomous degeneration of rods, preventing rod death would indirectly prevent central vision loss. The physiopathology of retinitis pigmentosa has benefited from spontaneous rodent models, especially the rd1 mouse ⁽¹⁴⁾. The rd1 mouse carries a recessive mutation in the Pde6b gene that encodes for the beta—subunit of the rod-specific phosphodiesterase that hydrolyses cyclic GMP (cGMP) in GMP upon light stimulation. This genetic defect leads to a non-physiological increase in cGMP concentration in rods that triggers somehow apoptosis. Photoreceptors maturate after birth in the mouse retina. Elevated cGMP is detected by post-natal (PN) day 8, and by PN21, all rods are lost. The model was originally used to identify gene with rod-specific expression by differential display of mRNA, but attempts to reverse the visual phenotype of the mouse was only successfully achieved by using corrective gene therapy approaches that reintroduce a copy of the normal Pde6b cDNA ⁽¹⁵⁾. It was proposed that multiple pathways are activated during rod apoptosis in the rd1 mouse and consequently targeting pharmacologically only one of these pathways is rather inefficient ⁽¹⁶⁾. This is the rational that led Ly et al. to study the kinetics profile of the proteome of the rd10 mouse ⁽¹⁾. The rd10 carries a recessive mutation in the Pde6b gene, as the rd1 mouse, but with a missense mutation in exon 13 of Pde6b gene, an allele that has some residual phosphodiesterase activity contrarily to the former which carries a null allele ⁽¹⁷⁾. As a consequence, rod degeneration is slower in the rd10 retina and light responses can be recorded even one month after birth ⁽¹⁸⁾.

The retina is the only part of the brain where neurons are ordered in regular layers in which cells can be identified easily on sections though their position. In addition, the retina is dissected very efficiently and precisely because the outer retina that is composed of photoreceptors, rods and cones, adheres to the RPE through their outer segments, a link that can be disrupted to separate the retina while preserving its integrity. Under standard procedures all the layers from the whole surface of the retina of a wildtype mouse are evenly represented in each specimen. This allows accurate differential expression analysis. The transcriptome of mouse models of retinitis pigmentosa was first studied and revealed biologically significant changes in gene expression in rods and later in cones of the rd1 retina ^(19,20). All retinal cell types respond during the process of retinal degeneration, while genes expressed specifically by photoreceptors (photoreceptor genes) have a reduced expression due to the loss of these cells, an injury response was observed from cells located in the inner retinal among which some endogenous neuroprotective genes. While being informative, the loss of expression of photoreceptor genes is indicative of the timing of the degenerative process, but it does not reveal the underlying mechanisms. Because of the chain reaction of the genomic response to photoreceptor degeneration, it is not possible to distinguish within the data, changes that are regulators of the apoptosis cascade from secondary events. One approach to the question would be to perform a kinetics analysis of the transcriptome of retina while degenerating in order to identify earliest events, then to inactivate these key regulator genes or to silence them and to validate their role in the death of photoreceptors. While technically feasible, this demonstration is still lacking. One could argue that following the elevation of cGMP, rod degeneration  is initiated at the levels of the proteins. Transcriptomic analysis is best suited to analysis developmental processes where the organ is constructed, but proteomics is a better option to study degenerative processes, for organ deconstruction. Ly et al. applied this kinetic approach to study the proteome of the retina of the rd10 mouse during rod degenerative process. The proteome of the end stage rod degeneration of the rd1 retina was previously reported ⁽²¹⁾. While the sensitivity of proteomics is still lagging behind that of transcriptomics, it is in constant progression over the last decade. Using filter-associated sample preparation protocol and a liquid chromatographic separation of the tryptic peptides followed by MS/MS analysis on a LC-MS/MS analysis on LTQ OrbitrapXL Ly et al. identified a total of 2,885 different proteins, among which 2,620 were quantified ⁽¹⁾. The data demonstrate that the approach paid off: at PN14, before any sign of rod degeneration can be observed in the rd10 retina, only two proteins were found to be significantly differentially expressed between the rd10 and the wild-type mouse. The reduced expression of PDE6G, a protein that is part of the phosphodiesterase complex is maybe a consequence of the PDE6B mutation rather than a consequence of the degenerative process. The authors concluded that the proteome does not reveal sign of degeneration at this stage. This is not the situation at PN28, when a total of 1,359 significant differences in protein expression have been identified between the two genotypes: the process is well advanced at this stage. The authors then focused their attention on the data at PN21, when only 57 significant changes were observed. The existence of 10 proteins expressed in photoreceptors with reduced expression at PN21 in that list (SAG, ABCA4, PROM1, CNGB1, BBS4, CNGA1, RGS9BP, PRPH2, ROM1, PDE6A) in addition to PDE6G reduced at PN14 and PEDE6B, the mutated protein, indicates that the process of degeneration is initiated in a significant proportion of rods by PN21. Mutations in the genes encoding for all of these proteins are causing retinitis pigmentosa or/and other inherited retinal dystrophies ⁽²⁾. The authors then used bioinformatics methods to cluster the data and to draw an interaction map that points on the implication of STAT signaling in rod degeneration, an observation that was validated in additional experiments. One could argue that interaction maps are based on prior knowledge and that important data may be outside the scope of such analysis, but the data now exist. Genes that are well studied exert an attraction in such analysis that is independent of their real implication in the biological process under scrutiny. Given the fact the increased STAT1 immunoreactivity matches that of a Muller glial cell marker, the induction of this signaling might still belong to the injury response to rod cell death. Due to the increasing power of proteomic instruments, it is very likely the question of the mechanisms of rod degeneration in mouse models of retinitis pigmentosa will be resolved in the near future. Post-translational modifications of proteins such as phosphorylations are analyzed more accurately by current instruments. Techniques to capture oxidation status of proteins, known as redox proteomics, are emerging ⁽²²⁾.