Table 3.
Candidate “Macro -Pathway” | Description of pathway activity and/or impairment | References |
---|---|---|
INFLAMMATION | Initial aggressive response by preformed cellular mediators, leading to increased inflammasome activity when macrophages accumulate in Bruch’s membrane | [48–53] |
MITOCHONDRION | Promoted mitochondrial outer membrane permeabilization could induce apoptosis, increase of ROS and mtDNA mutations | [54,55] |
RNA PROCESSING | RNA maturation enzyme alterations, such in U4/U6.U5 tri-snRNP complex | [56,57] |
CIRCADIAN RHYTHMS | Dysregulation of shed POS phagocytosis, with following disk shedding and accumulation of lipofuscin | [58–63] |
EPIGENETIC | Up – regulation of methylation – related genes | [64–66] |
FATTY ACID METABOLISM | Peroxidation of the LC – PUFAs and lipofuscin accumulation | [67–69] |
OXIDATIVE STRESS | Altered balance of oxidant/antioxidant activity | [10,70] |
APOPTOSIS AND CELL DEATH | Increased apoptosis and autophagy | [71] |
CYTOSKELETON AND VESICULAR TRAFFICKING | Alteration in retinal vesicular trafficking mediated by connecting cilium and cytoskeleton rearrangement (e.g. disruption of actin microfilament junctions between adjacent POSs or microtubule depolarization) | [72–76] |
PROTEOSTASIS | Misfolding of proteins involved into retinal survival and vision process, with deactivation of several chaperones | [77–81] |
SIGNAL TRANSDUCTION | Block of ciliary targeting of several proteins in photoreceptors and of ionotropic glutamate receptors in RGCs | [82–84] |
PHOTOTRANSDUCTION | Several RPE proteins, such as membrane frizzled – related protein (MFRP/Mftp) or the beta – V spectrins significantly modulate the expression of genes involved in phototransduction, impairing rod and cone functions when mutated | [85–87] |
NEURON | Reprogramming of RPE to differentiate towards retinal neurons and alteration of synaptic plasticity | [88–90] |
SPLICING |
Decrease of normal splicing (generally high in the retina) |
[91,92] |
PATHWAYS INVOLVING ALREADY KNOWN RP- ASSOCIATED GENES |
DESCRIPTION OF PATHWAY ACTIVITY AND/OR IMPAIRMENT |
REFERENCES |
ER STRESS AND UPR (ATF6, BBS10, PRPF8, TOPORS, SNRNP200, WFS1, KLHL7) |
Persistence of ER stress induces UPR to trigger intrinsic apoptotic pathway | [93–102] |
VESICULAR TRAFFICKING CONTROL (NPHP3, INVS, DHDDS, PNPLA6) |
Attempt to renew damaged cellular components involved in vesicular trafficking | [103–107] |
SPECIFIC TF REGULATIVE NETWORK (ZNF513, NR2F1) |
Impairment of opsin expression and possible adaptive protection from lipid deposits | [108–110] |
ECM REMODELING (TIMP3, COL11A1) |
ECM alterations, due to over – expression of pro – fibrotic proteins and matrix metalloproteinases, could induce apoptosis | [111–114] |
CELLULAR CYCLE REGULATION (PLK4, KIF11, CERKL, RB1CC1) |
Alterations in mitotic spindle development and cell cycle progression, as well as increased apoptosis and autophagy | [115–118] |
PHAGOCYTOSIS AND MELANOSOMES TRANSPORT IN RPE (MYO7A) |
Accumulation of waste components of photoreceptor outer segment, leading to apoptosis | [119–121] |
RETINOIC ACID CYCLE (RDH5, MKV) |
Block of redox reactions needed for visual cycle | [122–125] |
This table shows molecular details about how analyzed pathways could lead to retinal cell death.