Epigenetic adaptation prolongs photoreceptor survival during retinal degeneration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA563908 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10067868.fastq.gz | Fastqsanger.gz | |||
| SRR10067869.fastq.gz | Fastqsanger.gz | |||
| SRR10067870.fastq.gz | Fastqsanger.gz | |||
| SRR10067871.fastq.gz | Fastqsanger.gz | |||
| SRR10067872.fastq.gz | Fastqsanger.gz |
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Project description:Primary and secondary cone photoreceptor cell death in retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, leads to severe vision impairment and blindness. Regardless of the fact that protection of cone photoreceptor cells under stress conditions, such as retinal degenerative diseases, is crucial for maintaining vision, the underlying molecular mechanisms are unclear. Here, we investigated the function of the deubiquitinase Otud7b/Cezanne in the retina. We identified that Otud7b is predominantly expressed in photoreceptor cells in the mouse retina. While the ablation of Otud7b did not cause a significant defect in development and maturation of the mouse retina, Otud7b‒/‒ mice subjected to light-induced damage, which is one of the dry age-related macular degeneration models, exhibited increased cone photoreceptor degeneration. In addition, Otud7b deficiency in Mak‒/‒ mice, a retinitis pigmentosa mouse model, resulted in further cone photoreceptor degeneration. Moreover, neuronal cells deficient in Otud7b were susceptible to serum starvation, resulting in cell death. We found that NF-κB activity is increased in the Otud7b‒/‒ retinas exposed to light by RNA-sequencing analysis. Luciferase reporter assay also demonstrated increased NF-κB activation in Otud7b-deficient neuronal cells under stress. The neuronal cell death resulting from Otud7b deficiency was suppressed through the inhibition of NF-κB. Furthermore, we observed that inhibition of NF-κB attenuated cone photoreceptor degeneration in the light-exposed Otud7b‒/‒ retina. Together, the current study suggests that Otud7b deubiquitinase protects cone photoreceptor cells under stress conditions by modulating the NF-κB activity.
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Project description:Due to the high energy demands and characteristic morphology, retinal photoreceptor cells require a specialized lipid metabolism for survival and function. This study focused on the roles of saturated fatty acids and their metabolism. A frameshift mutation of lysophosphatidylcholine acyltransferase 1 (Lpcat1), introducing saturated fatty acids into lysophosphatidylcholine to produce disaturated phosphatidylcholine (PC), has been reported to cause spontaneous retinal degeneration in mice (rd11 mice). In this study, we performed a detailed characterization of Lpcat1 in the retina and found that Lpcat1 deficiency induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of the retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 affects disaturated PC production and the proper cellular fatty acid flux, presumably by altering saturated fatty acyl-CoA availabilities. Furthermore, we demonstrated that Lpcat1 deletion increased mitochondrial reactive oxygen species (ROS) levels in photoreceptor cells, but not in other retinal cells without affecting the OS structure and trafficking of OS-localized proteins. These results suggest that the LPCAT1-dependent production of disaturated PC is critical for metabolic adaptation during photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.
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Project description:Due to the high energy demands and characteristic morphology, retinal photoreceptor cells require the specialized lipid metabolism for survival and functions. In this study, we focus on the roles of saturated fatty acids and their metabolism in these processes. Frame-shift mutation of lysophosphatidylcholine acyltransferase 1 (Lpcat1), which introduces saturated fatty acid into lysophosphatidylcholine to produce disaturated phosphatidylcholine (PC), has been reported as a causative for spontaneous retinal degeneration in mice (rd11 mice). However, the molecular basis of retinal degeneration caused by Lpcat1 mutation remains unclear. Here, we report that Lpcat1 deficiency induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 affects not only disaturated PC production, but also the proper cellular fatty acid flux presumably through altering saturated fatty acyl-CoA availabilities. Furthermore, we demonstrated that Lpcat1 deletion increased mitochondrial reactive oxygen species (ROS) levels in photoreceptor cells, but not in other retinal cells, without affecting the OS structure and trafficking of OS localized proteins. These results suggested that LPCAT1-dependent production of disaturated PC is critical for metabolic adaptation during photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.
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2024-08-08 | GSE269514 | GEO
Project description:Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from an improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal disease. Here we utilized human organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.
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Project description:Retinal degeneration is a collection of devastating conditions with progressive loss of vision which often lead to blindness. Research on retinal microglial cells offers great therapeutic potential in deterring the progression of the condition. This study explored the mechanisms underlying the TREM2-mediated protective function of activated microglial cells during retinal degeneration. A significant upregulation of disease-associated microglia signature genes was observed during photoreceptor degeneration.
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Project description:Retinal degeneration is the leading cause of irreversible blindness. Retinitis pigmentosa (RP) is a genetically heterogenous group of diseases. In the United States, approximately one in 4000 individuals is affected. RP begins with the loss of night vision due to the loss of rod photoreceptor cells. The disease progresses slowly with the loss of peripheral vision, and eventually leads to complete debilitating and irreversible blindness. The first mutation associated with human RP was identified in the gene encoding rhodopsin, the G-protein coupled receptor of rod photoreceptor cells. Mutations within the rhodopsin gene account for significant portion of RP cases. Specifically, mutations of the proline at residue 347 in rhodopsin have been linked to human RP. We are fortunate to have access to the P347S rhodopsin mutant mice. These mice represent an excellent transgenic mouse model of retinal degeneration. The P347S rhodopsin mutation is one of the best studied mutations, yet the mechanism by which the mutation causes degeneration is still unknown. One study has demonstrated that galectin-1 plays a role in degeneration of neuronal processes (1) and another study has shown that expression level of galectin-3 is elevated in retinas of patients with age-related macular degeneration. These studies in conjunction with the availibility of the P347S mutant mice have provided impetus to examine the pathogenesis of retinal degeneration in the context of the possible role of glycans and glycan-binding proteins. The time course of photoreceptor degeneration in the P347S mouse model has been carefully studied. In these mice, degeneration is barely detectable at 1 month of age, yet biochemical evidence suggests that the rod photoreceptor cells have already begun to die. At 4 months of age, approximately half of the rod photoreceptor cells have degenerated. To distinguish involvement of glycogens at the various stages of retinal degeneration, we have collected retinas of wild type and the mutant mice at four time points (1, 2, 3, and 4 months of age). This will allow us to identify the genes that target early, mid- and late stages of the retinal degeneration process. Thus we request the analysis of total 24 samples as specified below: Age Group (months) Mice No of samples at each time point 1 Wild type 3 2 Wild type 3 3 Wild type 3 4 Wild type 3 1 P347S 3 2 P347S 3 3 P347S 3 4 P347S 3 Total 24.
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