Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP

Power, Michael; Das, Soumyaparna; Schütze, Karin; Marigo, Valeria; Ekström, Per; Paquet-Durand, François

doi:10.1016/j.preteyeres.2019.07.005

Cited by 97 publications

(140 citation statements)

References 367 publications

(496 reference statements)

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“…PARP1 is a key element in two forms of regulated necroptotic cell death termed parthanatos and cGMP-dependent cell death. The former has been strongly linked to Parkinson's disease 42,43 , and the latter in photoreceptor dystrophies 44 . These data are highly intriguing, emphasizing a need for further investigations of the cell death pathways elicited by the NTR/MTZ system to clarify relevance to degenerative disease mechanisms.…”

Section: Discussionmentioning

confidence: 99%

NTR 2.0: a rationally-engineered prodrug converting enzyme with substantially enhanced efficacy for targeted cell ablation

Sharrock

Mulligan

Hall

et al. 2020

Preprint

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Heterologously-expressed bacterial nitroreductase (NTR) enzymes sensitize eukaryotic cells to prodrugs such as metronidazole (MTZ), enabling selective cell ablation paradigms that have expanded studies of cell function and regeneration in vertebrate systems. However, first-generation NTRs require confoundingly toxic prodrug treatments (e.g. 10 mM MTZ) and some cell types have proven resistant. We used rational engineering and cross-species screening to develop a NTR variant, NTR 2.0, which exhibits ~100-fold improvement in MTZ-mediated cell-specific ablation efficacy. Toxicity tests in zebrafish showed no deleterious effects of prolonged MTZ treatments of ≤1 mM. NTR 2.0 therefore enables sustained cell loss paradigms and ablation of previously resistant cell types. These properties permit enhanced interrogations of cell function, extended challenges to the regenerative capacities of discrete stem cell niches, and enable modeling of chronic degenerative diseases. Accordingly, we have created a series of bipartite transgenic resources to facilitate dissemination of NTR 2.0 to the research community.

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Section: Discussionmentioning

confidence: 99%

NTR 2.0: a rationally-engineered prodrug converting enzyme with substantially enhanced efficacy for targeted cell ablation

Sharrock

Mulligan

Hall

et al. 2020

Preprint

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“…Further, the allelic series highlighted a non-apoptotic cell death mechanism involving calpain rather than the expected caspase-mediated apoptotic process [179]. Both elevated cGMP and calpain activation have been observed in other mouse RD models [181]. Thus, allelic series as used in these studies are informative for assessing disease mechanisms and identifying potential differences in treatment efficacy that may reflect disease severity.…”

Section: Category 02: Visual Transductionmentioning

confidence: 91%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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“…50 In recent years, the existence of necroptosis, ferroptosis, PARthanatos, and pyroptosis has been demonstrated as drivers of necrotic cell death during retinal degenerations in age-related macular degeneration or RP. [51][52][53][54] Necroptosis is regulated necrosis mediated by death receptors. Typically, necroptosis starts by stimuli such as TNFα, which binds to its receptors leading to RIPK1 activation.…”

Section: A Single Dose Of Intravitreal Adalimumab Reduced Nlrp3 Infmentioning

confidence: 99%

“…Nevertheless, we cannot exclude that other contributors such as calpains, may play a role in these events. 111 RIPK3 could promote NLRP3 inflammasome activation and in turn cell death through non-necroptotic mechanisms (eg, pyroptosis). Cell death processes and the relationship between each other during retinal degeneration in RP are very complex.…”

mentioning

confidence: 99%

Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice

et al. 2020

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Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by the progressive and irreversible loss of vision. We previously found that intraperitoneal administration of Adalimumab, a monoclonal anti‐TNFα antibody, slowed down retinal degeneration in the murine model of RP, the rd10 mice. The aims of this study were to improve its neuroprotective effect and to deepen understanding of the molecular mechanisms involved in this effect. We analyzed (i) the in vitro effect of Adalimumab on the TNFα‐mediated cell death in retinal cells; (ii) the effect of a single intravitreal injection of Adalimumab on retinal degeneration in rd10 mice at postnatal day (P) 23. In vitro studies showed that TNFα induced caspase and poly ADP ribose polymerase (PARP) activation, downregulation of (kinase receptor‐interacting protein 1) RIPK1 and upregulation of RIPK3 in retinal cells. Adalimumab reduced cell death probably through the inhibition of caspase 3 activation. In vivo studies suggested that PARP and NLRP3 inflammasome are mainly activated and to a lesser extent caspase‐dependent mechanisms in rd10 retinas at P23. Necroptosis seems to be inhibited by the downregulation of RIPK1. Adalimumab prevented from retinal degeneration without affecting caspase ‐dependent mechanisms but decreasing PARP activation, microglia activation as well as NLRP3 inflammasome.

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Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP

Cited by 97 publications

References 367 publications

NTR 2.0: a rationally-engineered prodrug converting enzyme with substantially enhanced efficacy for targeted cell ablation

NTR 2.0: a rationally-engineered prodrug converting enzyme with substantially enhanced efficacy for targeted cell ablation

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice

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