Skip to main content
. 2018 Dec 28;18(1):84–104. doi: 10.1080/15384101.2018.1558873

Table 4.

Detailed analysis of new candidate genes and their possible impact on RP etiopathogenesis.

New candidate genes – related pathways Description of pathway activity and/or impairment and of new candidate genes involved in References
CELL CYCLE REGULATORS Cell cycle proteins (CDKs) and their inhibitors’ (from Ink and Cip/Kip families) alterations could determine neuron death but, because they are usually expressed at a late stage of cell death, they could also attempt to save cells. As evidenced by our results, the up – regulation of CDKs 1, 4 and 6, with the contemporary down – expression of the only CDK5, could increase the apoptotic cell rate, mediated by a possible accumulation of phospho – Rb and p53. This cell death stimulation could be additionally enforced by the down – expression of CDKN2D and the over – expression of CDKN1B. [93,126134]
ZINC FINGERS TRANSCRIPTION FACTORS The main ZNFs transcription factor cluster suggested us that the cell proliferation is highly inhibited but, in the meantime, the down – expression of ZNF580 and ZFPM-1 could increase angiogenesis and phagocytosis. Probably the arrest of cell cycle could reduce oxidative damages induced by oxLDL, with increase of contemporary altered cells phagocytosis followed by neoangiogenesis, in order to attempt a final rescue of retinal tissue. [135146]
VESICULAR TRAFFICKING AND CELL MIGRATION RHOD and RRAS2 are two of most important hub genes of GTPase family. The down – expression of RHOD could impair migration and proliferation of RPE cells. At the same time, the over – expression of RRAS2 indicates an increase in cell spreading, probably related to a possible increased chemotaxis of inflammatory cells. [147149]
CHAPERONES, UPR AND ER STRESS The over – expression of XBP1 and ASF1A, together with down – expression of APC11 and PCBP1, indicate a possible increased apoptosis, induced by cell cycle regulator impaired ubiquitination, translation arrest and epigenetic instability. Additionally, the UPR activation and an attempt to correct protein folding could be favorite by the over – expression of DNAJC10. The down – expression of HSPA1A could be explained considering the reduction of the synthesis of proteins substrate of Hsp70. [48,150163]
SMALL GTPASE SUPERFAMILY ALTERED SIGNALLING Under stress conditions KRAS (already known to be involved in Noonan syndrome) up – regulation could determine an uncontrolled RPE cell proliferation or functional alterations. [164167]
INFLAMMATION A down – expression of BCL-3 in RPE cells exposed to the oxidant agent could lead to a cell proliferation arrest. Furthermore, the over-expression of INHBA, related to the TGF-β pathway, could imply vision loss arising from the transition between inflammation and cell death. [168173]
RETINOIC ACID EFFECTS ON EPIGENETICS An over – expression of SUV39H2, a histone methyltransferase that inhibits cytokines expression, could impair inflammatory responses and improve cellular homeostasis, probably as a defensive attempt to survive, after serious induced stress. [174176]
DNA BREAKS REPAIR SIRT1 resulted over – expressed in our experiment, highlighting how injured cells try to fight their damaging cause, by increasing antinflammatory activities and, above all, by improve the ability to repair DNA. Such molecular adaptations, combined with an increased neurotrophic response and a better regulation of lipid metabolism, could give RPE cells a fundamental neuroprotection, required to avoid retinal degeneration. [177186]
EARLY RESPONSE TO OXIDATIVE STRESS COULD IMPAIR SYNAPSES EGR-1, significantly reduced after oxLDL treatment, could impair retinal cells growth and differentiation and, very interestingly, disrupt synaptic communications. [187196]
FATTY ACIDS METABOLISM AND CIRCADIAN RHYTHMS NF-YA over-expression could alter the circadian rhythms regulation, as the daily cycle of Bmal1 expression and FASN signaling pathway. In order to link these results to RP pathogenesis, the altered FASN expression induced by oxidative stress may interfere with the normal RPE morphogenesis, leading to pathological phenotype. [197203]
MICROVASCULAR IMPAIRMENTS The over – expression of ITGA2 could represent one of the most interesting damage caused by oxLDL, which could imply the thrombosis of retinal microcirculation, leading to cell death. [204206]
CHROMOSOME INSTABILITY INDUCTION An over – expression of MAD2L1 could determine an early exit from mitosis. [207]
JUN COMPLEX AND RETINAL CELLS RESCUE The down – expression of JUN could improve the activation of AP – 1 complex, leading to an increased cellular proliferation, but without the possibility to rescue impaired retinal cells. [208210]
MITOCHONDRION – INDUCED APOPTOSIS Down-expression of HDAC10 suggests a relevant induction of mitochondrion – induced apoptosis of RPE cells. [211,212]