Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life

Lewandowski, Dominik; Sander, Christian; Tworak, Aleksander; Gao, Fangyuan; Xu, Qianlan; Skowronska‐Krawczyk, Dorota

doi:10.1016/j.preteyeres.2021.101037

Cited by 44 publications

(46 citation statements)

References 582 publications

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“…The metabolic pathways that lead to ceramide generation are the de novo synthesis pathway, the sphingomyelin hydrolysis pathway, or the salvage pathway in which complex sphingolipids are converted back to sphingosine and ceramide ( Figure 9A ). Increasing evidence suggests that elevated ceramide levels lead to photoreceptor degeneration, but overexpressing ceramidase or inhibiting ceramide generation pathways can rescue photoreceptor cells and prevent vision loss ( 15 , 29 , 45 , 54 – 58 ). Therefore, to test whether we could increase photoreceptor survival in AdipoR1 –/– mice, we decided to simultaneously inhibit 2 of the 3 ceramide generation routes, de novo biosynthesis and sphingomyelin hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision

Lewandowski¹,

Foik²,

Šmidák³

et al. 2022

JCI Insight

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Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with non-syndromic and syndromic retinitis pigmentosa. Here we show that the absence of AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, and reduced cone opsin expression. Single-cell RNA-Seq results indicated that ADIPOR1 encodes the most abundantly expressed ceramidase in mice and one of the two most highly expressed ceramidases in the human retina, next to acid ceramidase ASAH1. We discovered an accumulation of ceramides in the AdipoR1 -/retina, likely due to insufficient ceramidase activity for healthy retina function, resulting in photoreceptor death. Combined treatment with desipramine and L-cycloserine (DC) lowered ceramide levels and exerted a protective effect on photoreceptors in AdipoR1 -/mice. Moreover, we observed improvement in cone-mediated retinal function in the DC-treated animals. Lastly, we found that prolonged DC-treatment corrected the electrical responses of the primary visual cortex to visual stimuli, approaching near-normal levels for some parameters.These results highlight the importance of ADIPOR1 ceramidase in the retina, and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for ADIPOR1-related retinopathy.

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Section: Discussionmentioning

confidence: 99%

Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision

Lewandowski¹,

Foik²,

Šmidák³

et al. 2022

JCI Insight

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“…RPE cells are involved in the visual cycle, light absorption, nutrient transportation, and photoreceptor cell outer segment phagocytosis ( Sparrow et al, 2010 ; Ao et al, 2017 ). Dysfunctional RPE is the major cause of age-related retinal degeneration observed in the elderly population ( Fleckenstein et al, 2021 ; Lewandowski et al, 2021 ; Yang et al, 2021 ). In this study, we identified 192 potentially palmitoylated proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse carrying point mutation in Npc1 developed lipofuscin accumulation in the sub-RPE and sub-retina layers and photoreceptor degeneration at the age of 2 months ( Claudepierre et al, 2010 ). Abnormal lipid deposition of RPE cells is also associated with the development of blinding retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration (AMD) ( Pikuleva and Curcio, 2014 ; Veleri et al, 2015 ; Fleckenstein et al, 2021 ; Lewandowski et al, 2021 ; Ramachandra Rao and Fliesler, 2021 ). Although several studies have identified NPC1 as a palmitoylated protein in human and mouse cells and tissues (for a complete list of studies identified NPC1 as palmitoylted protein, see 1 ) ( Yang et al, 2010 ; Wilson et al, 2011 ; Morrison et al, 2015 ; Sanders et al, 2015 ; Serwa et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of s-acylated proteins in human retinal pigment epithelial cells and the role of palmitoylation of Niemann-Pick type C1 protein in cholesterol transport

Rao

Koh

et al. 2022

Front. Aging Neurosci.

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Palmitoylation is a dynamic process that regulates the activity of the modified proteins. Retinal pigment epithelial (RPE) cells play pivotal roles in the visual cycle and maintaining healthy photoreceptor cells. Dysfunctional RPE cells are often associated with degenerative retinal diseases. The aim of the study was to identify potentially palmitoylated proteins in human RPE cells. By using the detergent-resistant membrane, we found 312 potentially palmitoylated peptides which corresponded to 192 proteins in RPE cells, including 55 new candidate proteins which were not reported before. Gene enrichment analysis highlighted significant enrichment of palmitoylated proteins in cell-matrix adhesion, cell-cell recognition, protein cellular localization, and translation, among others. We further studied the effect of 3 potential palmitoylation sites (Cys 799, 900, and 816) of Niemann-Pick type C1 protein (NPC1) on cholesterol accumulation. We found that mutation of any single Cys alone had no significant effect on intracellular cholesterol accumulation while simultaneous mutation of Cys799 and 800 caused significant cholesterol accumulation in the late endosome. No further cholesterol accumulation was observed by adding another mutation at Cys 816. However, the mutation did not alter the cellular localization of the protein. Conclusion: PRE cells have an abundant number of palmitoylated proteins which are involved in cellular processes critical to visual function. The palmitoylation at Cys799 and 800 was needed for cholesterol export, but not the intracellular localization of NPC1.

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“…For example, approximately 700 lipid species were quantified and evaluated from mouse brains during aging and pathological conditions to identify cell-type and region-specific lipid profiles ( Fitzner et al, 2020 ). Similarly, the lipid composition of the eye, another part of the CNS, undergoes changes related to age and disease state ( Liu et al, 2010 ; Gorusupudi et al, 2016 ; Chen et al, 2020a ; Lewandowski et al, 2021a ).…”

Section: Introductionmentioning

confidence: 99%

“…Their dysregulation is associated with a variety of health conditions, including diseases and aging. Altered lipid metabolism results in changes in the membrane lipid environment, such as an age-related increased polyunsaturated fatty acid (PUFA) to monounsaturated fatty acid (MUFA) ratio, increased ceramide levels and decreased cholesterol levels ( Skowronska-Krawczyk and Budin, 2020 ; Lewandowski et al, 2021b ; Mutlu et al, 2021 ). While harmful lipid accumulation and peroxidation have been correlated with aging, emerging studies have only begun to explore the mechanistic link between lipid metabolism and pro-longevity signaling pathways ( Han et al, 2017 ; Qi et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Dynamic Progress in Technological Advances to Study Lipids in Aging: Challenges and Future Directions

2022

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Lipids participate in all cellular processes. Diverse methods have been developed to investigate lipid composition and distribution in biological samples to understand the effect of lipids across an organism’s lifespan. Here, we summarize the advanced techniques for studying lipids, including mass spectrometry-based lipidomics, lipid imaging, chemical-based lipid analysis and lipid engineering and their advantages. We further discuss the limitation of the current methods to gain an in-depth knowledge of the role of lipids in aging, and the possibility of lipid-based therapy in aging-related diseases.

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Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life

Cited by 44 publications

References 582 publications

Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision

Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision

Proteomic analysis of s-acylated proteins in human retinal pigment epithelial cells and the role of palmitoylation of Niemann-Pick type C1 protein in cholesterol transport

Dynamic Progress in Technological Advances to Study Lipids in Aging: Challenges and Future Directions

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