Cell Death Pathways in Mutant Rhodopsin Rat Models Identifies Genotype-Specific Targets Controlling Retinal Degeneration

Abstract

Retinitis pigmentosa (RP) is a group of inherited neurological disorders characterized by rod photoreceptor cell death, followed by secondary cone cell death leading to progressive blindness. Currently, there are no viable treatment options for RP. Due to incomplete knowledge of the molecular signaling pathways associated with RP pathogenesis, designing therapeutic strategies remains a challenge. In particular, preventing secondary cone photoreceptor cell loss is a key goal in designing potential therapies. In this study, we identified the main drivers of rod cell death and secondary cone loss in the transgenic S334ter rhodopsin rat model, tested the efficacy of specific cell death inhibitors on retinal function, and compared the effect of combining drugs to target multiple pathways in the S334ter and P23H rhodopsin rat models. The primary driver of early rod cell death in the S334ter model was a caspase-dependent process, whereas cone cell death occurred though RIP3-dependent necroptosis. In comparison, rod cell death in the P23H model was via necroptotic signaling, whereas cone cell loss occurred through inflammasome activation. Combination therapy of four drugs worked better than the individual drugs in the P23H model but not in the S334ter model. These differences imply that treatment modalities need to be tailored for each genotype. Taken together, our data demonstrate that rationally designed genotype-specific drug combinations will be an important requisite to effectively target primary rod cell loss and more importantly secondary cone survival.

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

“…Although photoreceptor death by apoptosis has been reported in models of retinal degeneration [ 7 , 8 , 11 , 12 ], there is growing evidence that caspase-independent cell death mechanisms are also involved in many blinding diseases, including RP. Indeed, some recent studies have suggested that these alternative mechanisms may be the dominant modes of cell death in RP [ 13 , 14 ]. Several forms of regulated necrosis have recently been described; including necroptosis, ferroptosis, pyroptosis and parthanatos [ 15 , 16 ].…”

“…Initiation of this process can occur by activation of cell death receptors, toll-like receptors, interferons or DNA damage sensors. Necroptosis has been implicated in both rod and cone degeneration in animal models of RP in several recent studies [ 14 , 20 , 21 , 22 ], discussed further below.…”

Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice

“…Several authors have proposed the upregulation of caspase 3/8 activities and mitochondrial cytochrome C release in RP models like transgenic S334ter rats, tubby mice, rds mice, etc. [76][77][78][79] However, other caspase 3-independent mechanisms have been reported for rod cell death in rd mice or P23H rats. 80,81 Double labeling with TUNEL and cleaved caspase 3 indicated that degenerating photoreceptors (TUNEL positive cells) were not cleaved-caspase 3 positive cells (an early event of apoptosis) at this age.…”

“…For instance, Viringipurampeer et al proposed that the primary driver of early rod cell death was a caspase-dependent process, whereas cone cell death occurred through RIPK3-dependent necroptosis in the transgenic S334ter rhodopsin. 77 The same authors described that primary necroptosis was involved in early rod cell death, whereas cone cell loss occurred through inflammasome activation in P23H rats. 77 Murakami et al 47 suggested that apoptosis occurred early, during rod degeneration but, RIPK3mediated necroptosis was responsible for cone degeneration at later stages (at P35 or later) in rd10 mice.…”

“…77 The same authors described that primary necroptosis was involved in early rod cell death, whereas cone cell loss occurred through inflammasome activation in P23H rats. 77 Murakami et al 47 suggested that apoptosis occurred early, during rod degeneration but, RIPK3mediated necroptosis was responsible for cone degeneration at later stages (at P35 or later) in rd10 mice. 47 Upregulation of RIPK1 and RIPK3 was found at the later stages of RP (P35) in rd10 retinas.…”