Mol Vis
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Neurotrophins, including nerve growth factor (NGF), are secreted by glia as a pro-form (proNGF) that is normally cleaved into the mature ligand. Increases of proNGF has been well documented in retinal neurodegenerative diseases. Since systemic overexpression of proNGF exhibits embryonic lethality, we aimed to establish a model that specifically and stably overexpresses a cleavage-resistant mutant of proNGF (proNGF123) plasmid in the retina using electroporation. ⋯ Electroporation can successfully incorporate and express biologically active cleavage-resistant proNGF locally in rat retinas. Overexpression of cleavage-resistant proNGF can be a useful tool to investigate specific molecular mechanisms by which proNGF causes neurodegeneration and vascular injury in the retina.
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Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin (OPN4) and are mainly responsible for non-image-forming visual tasks such as circadian photoentrainment and the pupillary light reflex. Compared to other classes of RGCs, ipRGCs are more resistant to cell death in several experimental models such as ocular hypertension, optic nerve transection, and others. Here, we tested whether ipRGCs are also resistant to N-methyl-D-aspartic acid (NMDA)-induced excitotoxicity. ⋯ Our data support the existence of an efficient survival system for ipRGCs. This system does not depend on PI3K/AKT or JAK/STAT signaling. Identification of the responsible molecular survival mechanisms may provide clues to protect "traditional" ganglion cells in diseases such as glaucoma.
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Survivin (Birc5) is the smallest member of the inhibitor of apoptosis (IAP) protein family, which regulates the cell cycle/apoptosis balance. The purpose of this study was to examine Survivin expression in the embryonic chick lens, in chick lens epithelial cell cultures, and in the postnatal mouse lens. ⋯ Survivin is expressed during chick and mouse lens development and in chick lens epithelial cell cultures. High levels of Survivin expression correlated with high rates of proliferation of lens epithelial cells at early stages of development. Downregulation of Survivin expression with development and its progressive localization to the nuclei of lens fiber cells was coincident with a decrease in cell proliferation and increased denucleation in differentiating lens fiber cells. These studies suggest an important role for Survivin as a dual regulator of lens epithelial cell proliferation and lens fiber cell differentiation.
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In our previous study, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) played a neuroprotective role in retinal ischemia/reperfusion (I/R) injury in rats. However, the mechanism of NF-κB neuroprotection is still unclear. We hypothesize that p38 mitogen-activated protein kinase (MAPK) is expressed and NF-κB activity induced by p38 MAPK plays a neuroprotective role through antiapoptotic genes (B-cell lymphoma [Bcl]-2 and Bcl-XL) in retinal cells in retinal I/R injury. ⋯ These findings provide evidence of crosstalk between p38 MAPK and NF-κB p65 and demonstrate a possible neuroprotective role for the p38 MAPK-NF-κB pathway through Bcl-2 and Bcl-XL in retinal I/R injury in rats.
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To evaluate genetic susceptibility of lysyl oxidase-like 1 (LOXL1) gene polymorphisms to exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) in a case-control cohort of American and European patients. ⋯ We confirmed a strong association with LOXL1 variants in our patients. For the LOXL1 gene, individual alleles of rs1048661 (G), rs3825942 (G), and rs2165241 (T) are highly associated with XFS and XFG in American and European populations. The GGT haplotype constitutes a major risk haplotype for exfoliation, and GAC may have a protective role. DNA sequencing of 95 affected patients did not show any mutations in this gene. The LOXL1 SNPs are located in the 15q24.1 band and within a genetic locus (GLC1N) that is associated with primary open-angle glaucoma (POAG). However, the LOXL1 genetic predisposition is only limited to exfoliation with or without glaucoma and does not include the POAG phenotype.