Programmed Non-Apoptotic Cell Death in Hereditary Retinal Degeneration: Crosstalk between cGMP-Dependent Pathways and PARthanatos?

Programmed cell death (PCD) is a highly regulated process that results in the orderly destruction of a cell. Many different forms of PCD may be distinguished, including apoptosis, PARthanatos, and cGMP-dependent cell death. Misregulation of PCD mechanisms may be the underlying cause of neurodegenerative diseases of the retina, including hereditary retinal degeneration (RD). RD relates to a group of diseases that affect photoreceptors and that are triggered by gene mutations that are often well known nowadays. Nevertheless, the cellular mechanisms of PCD triggered by disease-causing mutations are still poorly understood, and RD is mostly still untreatable. While investigations into the neurodegenerative mechanisms of RD have focused on apoptosis in the past two decades, recent evidence suggests a predominance of non-apoptotic processes as causative mechanisms. Research into these mechanisms carries the hope that the knowledge created can eventually be used to design targeted treatments to prevent photoreceptor loss. Hence, in this review, we summarize studies on PCD in RD, including on apoptosis, PARthanatos, and cGMP-dependent cell death. Then, we focus on a possible interplay between these mechanisms, covering cGMP-signaling targets, overactivation of poly(ADP-ribose)polymerase (PARP), energy depletion, Ca2+-permeable channels, and Ca2+-dependent proteases. Finally, an outlook is given into how specific features of cGMP-signaling and PARthanatos may be targeted by therapeutic interventions.

Retinitis Pigmentosa; Epidemiology, Pathophysiology, and Classification

Retinitis pigmentosa (RP) is the most common hereditary retinal degeneration. It primarily affects rods and then cone photoreceptors. RP manifests with night blindness and concentric visual field loss, reflecting the dysfunction of rod photoreceptors. Central visual acuity loss occurs last period of disease due to cone dysfunction; otherwise, macula involvements like cystoid macular edema. Classically described fundus appearance of RP includes mottling and granularity of the retina pigment epithelium, bone spicule intraretinal pigmentation, attenuated retinal vessels, and optic disc head pallor. RP can be transmitted as Mendelian’s an autosomal dominant, autosomal recessive, or X-linked trait. Mitochondrial or digenic forms also rarely have been described. However, the sporadic or simplex form is the most commonly seen in the clinic. Recently great progress has been made in the identification of the causative genes. This review presents a comprehensive overview of the clinical, genetic, and fundus photography, optical coherence tomography, fundus autofluorescence, microperimetry dark adaptometer, and ocular electrophysiology characteristics of RP.

Stargardt and Fundus Flavimaculatus; Current and Developing Treatments

Stargardt macular dystrophy is a hereditary retinal degeneration that lacks effective treatment options. The pathophysiology of the disease is still not fully understood. While there are currently no available treatments for Stargardt disease, there are many categories of therapeutics under investigation to fulfill this unmet need for treatment. These include investigational visual cycle modulators, complement inhibitors, ABCA4 gene therapy, and subretinal transplantation of stem cell-derived retina pigment epithelial cells. Further trials are warranted to assess efficacy and safety in humans. In this review, the treatments investigated for the Stargardt disease are explained.

Systematic spatio-temporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration

Calcium (Ca2+) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca2+ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis.We examined the role of Ca2+ in photoreceptor degeneration, assessing the activation pattern of Ca2+-dependent calpain proteases, generating spatio-temporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources.In the rd1 and rd10 models, spatio-temporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain-2 isoform but not with calpain-1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis-inducing factor (AIF), although only a minute fraction of cells showed activity of the apoptotic marker caspase-3. After primary rod degeneration concluded, caspase-3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death.Our data suggests a causal link between Ca2+ dysregulation and primary, non-apoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.