General pathophysiology in retinal degeneration

Abstract

Retinal degeneration, including that seen in age-related macular degeneration and retinitis pigmentosa (RP), is the most common form of neural degenerative disease in the world. There is great genetic and allelic heterogeneity of the various retinal dystrophies. Classifications of these diseases can be ambiguous, as there are similar clinical presentations in retinal degenerations arising from different genetic mechanisms. As would be expected, alterations in the activity of the phototransduction cascade, such as changes affecting the renewal and shedding of the photoreceptor OS, visual transduction, and/or retinol metabolism have a great impact on the health of the retina. Mutations within any of the molecules responsible for these visual processes cause several types of retinal and retinal pigment epithelium degenerative diseases. Apoptosis has been implicated in the rod cell loss seen in a mouse model of RP, but the precise mechanisms that connect the activation of these pathways to the loss of phosphodiesterase (PDE6β) function has yet to be defined. Additionally, the activation of apoptosis by CCAAT/-enhancer-binding protein homologous protein (CHOP), after activation of the unfolded protein response pathway, may be responsible for cell death, although the mechanism remains unknown. However, the mechanisms of cell death after loss of function of PDE6, which is a commonly studied mammalian model in research, may be generalizable to loss of function of different key proteins involved in the phototransduction cascade.

Fig. 1

Histological section of the retina. Hematoxylin and eosin-stained section of a C57BL/6J wild-type mouse retina depicting the various cell layers. GCL = Ganglion cell layer; IPL = inner plexiform layer; INL = inner nuclear layer; OPL = outer plexiform layer; ONL = outer nuclear layer.

Fig. 2

Phototransduction cascade. a Key genes involved in the phototransduction cascade during the dark, where cGMP is maintained within the rod photoreceptor cell and the CNG channels are open to allow an influx of sodium ions and Ca²⁺. b Key genes involved in the phototransduction cascade during light stimulation, where the cascade is activated leading to the breakdown of cGMP and the closure of the CNG channels.

Fig. 3

UPR pathway. The three integral membrane proteins that are activated to initiate the UPR pathway: PERK, ATF6 and IRE1. PERK = Pancreatic ER eIF2α kinase; K = RNA-binding domain; ATF6 = activating transcription factor 6; bZIP = basic leucine zipper domain; R = regulatory domain.