Table 3.

Possible roles of candidate “macro – pathways” and pathways involving already known RP – associated genes towards retinal cells death.

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.