Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.

Prion-induced photoreceptor degeneration begins with misfolded prion protein accumulation in cones at two distinct sites: cilia and ribbon synapses

“…The association of PrPSc with cilia may be an important clue to the pathogenic process of prion infection in retina. This abnormal accumulation might interfere with or damage the ciliary protein transport system between the IS and OS regions of photoreceptors as has been proposed in retinitis pigmentosa and ciliopathies [ 34 , 40 ]. In support of this mechanism, we found unusual distributions of opsin and cone arrestin (Figs.…”

“…Photoreceptors are also damaged in human retinitis pigmentosa, which is a major cause of human blindness resulting in a retinal pathology similar to prion diseases. In some forms of retinitis pigmentosa, microglia are known to become activated by the misfolding of mutant host proteins such as rhodopsin, and microglia have also been suspected to be important in the pathogenic process [ 40 , 46 ]. In prion diseases, microglia activated by the deposition of aggregated prion protein have also been suspected to be a possible mechanism of pathogenesis [ 18 ].…”

Metabolic Analysis of Vitreous/Lens and Retina in Wild Type and Retinal Degeneration Mice

“…Alternatively, 3-Hydroxybutyrate could concur to the antioxidative stress response of photoreceptors [ 48 , 49 ], particularly acting together with Fumarate [ 45 ], which we also found increased in the Rd1 mutant retina at eye opening when compared to the wt condition. Oxidative stress is known to play a key role in retinal degeneration and has been the target of several therapeutic approaches [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. The exceptional metabolic demand of photoreceptors is paralleled by a combination of different metabolic pathways, including primarily aerobic glycolysis [ 7 , 8 , 9 , 12 ], but also oxidative phosphorylation [ 2 , 14 , 15 ], which when combined with light exposure is one potential source of reactive oxygen species within these cells.…”

Fructus lycii: A Natural Dietary Supplement for Amelioration of Retinal Diseases

“…RP is a heterogeneous group of inherited bilateral retinal pigmentary dystrophies that are characterized by progressive and sequential loss of rod and cone photoreceptors, ultimately leading to complete blindness [ 94 ]. Several mechanisms have been linked to triggering the death of photoreceptors in mouse models of RP, such as oxidative stress, ER stress, dysregulation of cyclic guanosine monophosphate (cGMP) signalling, accumulation of calcium ions, and inflammatory responses [ 95 ]. Oxidative stress may be a crucial pathway because of the following reasons: first, the retina is highly vulnerable to oxidative stress; second, antioxidant treatment improves cell survival and preserves photoreceptors function in animal models; third, antioxidant treatment may decrease inflammatory markers involved in apoptosis [ 96 ].…”