bims-mideyd 2022-09-25 papers

Issue of 2022‒09‒25
four papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Acta Ophthalmol. 2022 Sep;100 Suppl 269 3-43

PURPOSE: The retina has enormous lipids demands and must meet those needs. Retinal lipid homeostasis appears to be based on the symbiosis between neurons, Müller glial cells (MGC), and retinal pigment epithelium (RPE) cells, which can be impacted in several retinal diseases. The current research challenge is to better understand lipid-related mechanisms involved in retinal diseases, such as age-related macular degeneration (AMD) and glaucoma.RESULTS: In a first axis, in vitro and focus on Müller glial cell, we aimed to characterize whether the 24S-hydroxycholesterol (24S-OHC), an overexpressed end-product of cholesterol elimination pathway in neural tissue and likely produced by suffering retinal ganglion cells in glaucoma, may modulate MGC membrane organization, such as lipid rafts, to trigger cellular signalling pathways related to retinal gliosis. We have found that lipid composition appears to be a key factor of membrane architecture, especially for lipid raft microdomain formation, in MGC. However, 24S-OHC did not appear to trigger retinal gliosis via the modulation of lipid or protein composition within lipid rafts microdomains. This study provided a better understanding of the complex mechanisms involved in the pathophysiology of glaucoma. On a second clinical ax, we focused on the lipid-related mechanisms involved in the dysfunction of aging RPE and the appearance of drusenoid deposits in AMD. Using the Montrachet population-based study, we intend to report the frequency of reticular pseudodrusen (RPD) and its ocular and systemic risk factors, particularly related to lipid metabolisms, such as plasma lipoprotein levels, carotenoids levels, and lipid-lowering drug intake. Our study showed that RPD was less common in subjects taking lipid-lowering drugs. Lipid-lowering drugs, such as statins, may reduce the risk of RPD through their effect on the production and function of lipoproteins. This observation highlights the potential role of retinal lipid trafficking via lipoproteins between photoreceptors and retinal pigment epithelium cells in RPD formation. Those findings have been complemented with preliminary results on the analysis of plasma fatty acid (FA) profile, a surrogate marker of short-term dietary lipid intake, according to the type of predominant drusenoid deposit, soft drusen or RPD, in age-related maculopathy.
CONCLUSION: Further research on lipid metabolism in retinal diseases is warranted to better understand the pathophysiology of retinal diseases and develop new promising diagnostic, prognostic, and therapeutic tools for our patients.

Keywords: Müller glial cell; age-related macular degeneration; cholesterol; glaucoma; lipid raft; lipids; lipoprotein; omega 3; polyunsaturated fatty acids; retinal gliosis; retinal pigment epithelium

DOI: https://doi.org/10.1111/aos.15226

Exp Eye Res. 2022 Sep 20. pii: S0014-4835(22)00334-7. [Epub ahead of print] 109254

Does senescence play a role in age-related macular degeneration?

Goldis Malek, Judith Campisi, Koji Kitazawa, Corey Webster, Aparna Lakkaraju, Dorota Skowronska-Krawczyk.

Advanced age is the most established risk factor for developing age-related macular degeneration (AMD), one of the leading causes of visual impairment in the elderly, in Western and developed countries. Similarly, after middle age, there is an exponential increase in pathological molecular and cellular events that can induce senescence, traditionally defined as an irreversible loss of the cells' ability to divide and most recently reported to also occur in select post-mitotic and terminally differentiated cells, such as neurons. Together these facts raise the question as to whether or not cellular senescence, may play a role in the development of AMD. A number of studies have reported the effect of ocular-relevant inducers of senescence using primarily in vitro models of poorly polarized, actively dividing retinal pigment epithelial (RPE) cell lines. However, in interpretating the data, the fidelity of these culture models to the RPE in vivo, must be considered. Fewer studies have explored the presence and/or impact of senescent cells in in vivo models that present with phenotypic features of AMD, leaving this an open field for further investigation. The goal of this review is to discuss the current thoughts on the potential role of senescence in AMD development and progression, considering the model systems used and their relevance to human disease.

Keywords: Age-related macular degeneration; Aging; Retinal pigment epithelium; Senescence

DOI: https://doi.org/10.1016/j.exer.2022.109254

Antioxidants (Basel). 2022 Aug 24. pii: 1642. [Epub ahead of print]11(9):

Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction.

Kerry C Ryan, Jocelyn T Laboy, Kenneth R Norman.

Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue SEL-12 results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1/Nrf. Our study reveals that SEL-12/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1/Nrf antioxidant activity.

Keywords: Alzheimer’s disease; Nrf2; calcium; mitochondria; neuronal dysfunction; oxidative stress; presenilin

DOI: https://doi.org/10.3390/antiox11091642

Curr Eye Res. 2022 Sep 23. 1-9

Paired Box Gene 6 Regulates Heme Oxygenase-1 Expression and Mitigates Hydrogen Peroxide-Induced Oxidative Stress in Lens Epithelial Cells.

Yuxing Zheng, Xiaoxi Yang, Shuduan Wu, Guoguo Yi, Xiaobo Huang, Zhizhen Feng, Lei Qu, Linyu Liu, Qianyun Li, Zhaoxia Xia.

PURPOSE: This study aimed to investigate the regulation of heme oxygenase-1 (HO-1) by paired box gene 6 (Pax6) and their roles in hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in lens epithelial cells (LECs) (SRA01/04, HLE-B3).METHODS: Lens anterior capsule membranes of mice of different ages were obtained to compare differences in the expression of Pax6 and HO-1 using Western blotting. Pax6-overexpressing plasmid and small interfering RNA were designed to overexpress and silence Pax6, respectively. Cobalt protoporphyrin (CoPP) was used to promote the expression of HO-1. Oxidative damage in LECs was induced by treatment with H2O2 (400 µM) for 24 h. Cell viability was measured using the Cell Counting Kit-8 assay. Intracellular reactive oxygen species (ROS) were detected using flow cytometry and immunofluorescence. Superoxide dismutase (SOD) level was measured using SOD Assay Kit and apoptotic cells were quantified using annexin V-fluorescein isothiocyanate/propidium iodide staining.
RESULTS: Pax6 and HO-1 expression levels showed an age-dependent decrease in LECs of mouse. Overexpressing Pax6 upregulated HO-1 expression level. Silencing Pax6 downregulated the HO-1 expression level, resulting in increased generation of ROS, reduced SOD activity, decreased cell viability, and increased apoptotic cells of LECs under H2O2-induced oxidative stress. Overexpressing Pax6 and CoPP both mitigates H2O2-induced oxidative stress by increasing the expression of HO-1 of LECs.
CONCLUSION: Pax6 and HO-1 expression levels showed an age-dependent decrease in LECs in mouse anterior capsules. Pax6 could regulate the expression of HO-1 in LECs. The decrease of Pax6 weakened the antioxidant ability of LECs under H2O2-induced oxidative stress by downregulating HO-1, which may be a potential mechanism for the formation of age-related cataract.

Keywords: Age-related cataract; heme oxygenase-1; lens epithelial cells (SRA01/04 HLE-B3); oxidative stress; paired box gene 6

DOI: https://doi.org/10.1080/02713683.2022.2110266