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The Importance of MicroRNA Expression in Pseudoexfoliation Syndrome.

ABSTRACT: Pseudoexfoliation syndrome (PEX) is an important systemic disorder of the extracellular matrix, in which granular amyloid-like protein fibers accumulate in the anterior segment of the eyeball as well as in other organs. PEX is currently considered to be a multifactorial systemic disorder with genetic and environmental risk factors. The aim of this manuscript was to analyze miR expression in PEX. In recent years, an attempt has been made to investigate and describe the level of expression of selected miRs in PEX. Four polymorphisms of genes isolated from the blood that may be related to PEX were identified and miR-122-5p was found to be upregulated in patient blood. Furthermore, 18 miRs were identified with a statistically different expression in the aqueous humor. A significantly elevated expression of miR-125b was found in the anterior lens capsule, and four miRs were described, which may have a significant impact on the development of PEX. Regulatory miR molecules are gaining more and more importance in research aimed at identifying and isolating molecular markers related to the pathogenesis and prognosis of PEX, but further studies are needed.

SUBMITTER: Tomczyk-Socha M

PROVIDER: S-EPMC9653611 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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The Importance of MicroRNA Expression in Pseudoexfoliation Syndrome.

Tomczyk-Socha Martyna M Tomczak Wojciech W Turno-Kręcicka Anna A

International journal of molecular sciences 20221031 21

Pseudoexfoliation syndrome (PEX) is an important systemic disorder of the extracellular matrix, in which granular amyloid-like protein fibers accumulate in the anterior segment of the eyeball as well as in other organs. PEX is currently considered to be a multifactorial systemic disorder with genetic and environmental risk factors. The aim of this manuscript was to analyze miR expression in PEX. In recent years, an attempt has been made to investigate and describe the level of expression of sele ...[more]

PMID: 36362020

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Project description:PurposeTo study lysyl oxidase-like 1 (LOXL1) expression in freshly collected lens capsules from pseudoexfoliation syndrome (XFS), pseudoexfoliation glaucoma (XFG), and normal cataract control individuals. We also investigated the effects of four glaucoma drug medications on LOXL1 expression in primary human lens epithelial cell cultures to see if they could affect LOXL1 expression.MethodsLens capsules were collected at the time of cataract surgery. Controls were matched to age, sex, and ethnicity. Total RNA was isolated from individual lens capsule samples and real-time PCR was performed on each sample using primers flanking the sixth exon of the LOXL1 gene. Cell cultures were grown to confluence in four separate six-well plates at 37 °C in 5% CO2. Each plate was then treated with one of four different glaucoma drugs (brinzolamide 1%, brimonidine tartrate 0.1%, timolol maleate 0.5%, and latanoprost 0.005%) once daily for seven days (at both 1:1,000 and 1:100 concentrations relative to media). Controls were not treated with any drug but media was changed in the same manner. After one week of treatment, cells were harvested and total RNA isolated. Real-time PCR was performed on each group of cells.ResultsSeven XFS, seven XFG, and ten cataract control specimens were analyzed. LOXL1 expression was detected in the lens capsule specimens from each of the four groups. Significant expression differences were found between the control and XFG groups and XFS and XFG groups. No significant difference was observed between the control and XFS group. No significant decrease in LOXL1 expression was seen with drug incubation of the four medications (Brinzolamide, Timolol, Latanoprost, and Brimonidine) at the 1:1,000 drug:media concentrations versus controls. At 10-fold higher concentrations (1:100 drug:media), brinzolamide, timolol maleate, and latanoprost showed small increases in LOXL1 expression relative to controls. This effect was not observed with brimonidine tartrate.ConclusionsThese results establish that LOXL1 expression is reduced in lens capsule specimens from XFG individuals but not XFS. The drug treatment incubation studies suggest that the change in LOXL1 expression observed in XFG is not attributable to glaucoma drug therapy. If a causative functional relationship can be validated, modification of LOXL1 expression in affected tissues may represent a novel treatment strategy for this disorder.

Project description:Pseudoexfoliation (PEX) syndrome, one of the most common causes of glaucoma, represents a complex, multifactorial, late-onset disease of worldwide significance. The etiopathogenesis involves both genetic and non-genetic factors. The PEX-specific tissue alterations are caused by a generalized fibrotic matrix process, which has been characterized as a stress-induced elastosis associated with the excessive production and abnormal cross-linking of elastic microfibrils into fibrillar PEX aggregates. The identification of lysyl oxidase-like 1 (LOXL1) as a major genetic risk factor for PEX syndrome and PEX glaucoma further supports a role of elastogenesis and elastosis in the pathophysiology of PEX, as LOXL1 is a pivotal cross-linking enzyme in elastic fiber formation and stabilization. The available data suggest that LOXL1 is markedly dysregulated depending on the stage of the fibrotic process. While transient upregulation of LOXL1 during the early stages of PEX fibrogenesis participates in the formation and aggregation of abnormal PEX fiber deposits, the decreased expression of LOXL1 during the advanced stages of the disease may affect elastin metabolism and promote elastotic processes, e.g. in the lamina cribrosa, predisposing to glaucoma development. However, in view of the low penetrance of the PEX-associated risk variants of LOXL1, other genetic and/or environmental factors must contribute to the risk of developing the PEX phenotype. Some evidence exists for the contribution of additional genes with relatively small effects, e.g. clusterin (CLU), contactin-associated protein-like 2 (CNTNAP2), apolipoprotein E (APOE), glutathione S-transferases (GSTs), and tumor necrosis factor-alpha (TNFA), in certain study populations. Several environmental conditions associated with PEX, such as oxidative stress as well as pro-fibrotic cytokines and growth factors, can regulate expression of LOXL1 and elastic proteins in vitro and may therefore act as co-modulating external factors. Ultimately, both detection and functional characterization of yet unidentified genetic and non-genetic factors may lead to the development of more precise screening tools for the risk of PEX glaucoma.

Dataset Information

The Importance of MicroRNA Expression in Pseudoexfoliation Syndrome.

Publications

The Importance of MicroRNA Expression in Pseudoexfoliation Syndrome.

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