LOXL1-associated Candidate Epithelial Pathomechanisms in Exfoliation Glaucoma

Laczkó, Rozália; Szauter, Kornélia Molnárné; Csiszár, Katalin

doi:10.1097/ijg.0000000000000105

Cited by 11 publications

(10 citation statements)

References 22 publications

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“…This is similar to other epigenetic regulators that have both enzymatic activity dependent and independent functions. For example, JMJD3, a well-known histone lysine demethylase has demethylase independent functions as well 40,41 , and the lysyl-oxidases LOXL1 and LOXL2 have enzymatic activity-independent functions in EMT 42,43 .…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses

Zhao

Adams

Weinman

et al. 2019

Sci Rep

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Protein Arginine methyltransferase 1 (PRMT1) is the main enzyme of cellular arginine methylation. Previously we found that PRMT1 activity in the liver is altered after alcohol exposure resulting in epigenetic changes. To determine the impact of these PRMT1 changes on the liver’s response to alcohol, we induced a hepatocyte specific PRMT1 knockout using AAV mediated Cre delivery in mice fed either alcohol or control Lieber-DeCarli liquid diet. We found that in alcohol fed mice, PRMT1 prevents oxidative stress and promotes hepatocyte survival. PRMT1 knockout in alcohol fed mice resulted in a dramatic increase in hepatocyte death, inflammation and fibrosis. Additionally, we found that alcohol promotes PRMT1 dephosphorylation at S297. Phosphorylation at this site is necessary for PRMT1-dependent protein arginine methylation. PRMT1 S297A, a dephosphorylation mimic of PRMT1 had reduced ability to promote gene expression of pro-inflammatory cytokines, pro-apoptotic genes BIM and TRAIL and expression of a suppressor of hepatocyte proliferation, Hnf4α. On the other hand, several functions of PRMT1 were phosphorylation-independent, including expression of oxidative stress response genes, Sod1, Sod2 and others. In vitro , both wild type and S297A PRMT1 protected hepatocytes from oxidative stress induced apoptosis, however S297D phosphorylation mimic PRMT1 promoted cell death. Taken together these data suggest that PRMT1 is an essential factor of liver adaptation to alcohol; alcohol-induced dephosphorylation shifts PRMT1 toward a less pro-inflammatory, more pro-proliferative and pro-survival form.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses

Zhao

Adams

Weinman

et al. 2019

Sci Rep

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“…Moreover, inflammation has also been suggested in migratory failure and subsequent deposition of aberrant proteinaceous materials in affected tissues in conjunction with other molecular actors. 71,[103][104][105][106][107][108] Finally, our comorbidity analysis in the BioVU EHR indicated XFS association with several chronic inflammatory dermatological, musculo-skeletal, respiratory and infectious conditions. Moreover, extracellular matrix dysregulation is also suggested by our PheWAS results indicating XFS comorbidity with Vitamin D deficiency.…”

Section: Discussionmentioning

confidence: 96%

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

Hirbo

Pasutto

Gamazon

et al. 2020

Preprint

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Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. We performed Transcriptomic Wide Association Studies using PrediXcan models trained in 48 GTEx tissues to identify genetically-determined gene expression changes associated with XFS risk, leveraging on results from a global GWAS that included 123,457 individuals from 24 countries. Twenty-eight genes in the chr15q22-25 region showed statistically significant associations in both single-tissue and multi-tissue analysis. Reduced models for these genes that excluded variants in LD with the known LOXL1 signal showed genome-wide significant association signals in nine genes, independently of LOXL1. Out of these ten genes, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. Genes with genetically determined expression changes in XFS were significantly enriched for genes associated with inflammatory conditions. We further explored the health consequences of high susceptibility to XFS using a large electronic health record and observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. Our results implicate a role for connective tissues and inflammation in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.

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“…Guo et al recently identified the LOX mutation that causes familial TAAD: the Ser280Arg mutation produced a less active variant that led to disorganised elastic fibres and increased collagen in patients’ aortas [127]. Several reports have described an association between LOXL1 and glaucoma, specifically in the early stages of the elastic fibre disorder exfoliation syndrome (XFS) [76,[128], [129], [130], [131]]. LOXL1 colocalised with elastin, fibrillin-1 and fibulin-4, which were also upregulated, and its expression was enhanced by TGFβ1 and other XFS-associated stimuli in Tenon’s capsule fibroblasts [76].…”

Section: Functional Modifiers Of Elastic Fibresmentioning

confidence: 99%

Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors

Thomson

Singh

Eckersley

et al. 2019

Seminars in Cell & Developmental Biology

117

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Fibrillin microfibrils are extensible polymers that endow connective tissues with long-range elasticity and have widespread distributions in both elastic and non-elastic tissues. They act as a template for elastin deposition during elastic fibre formation and are essential for maintaining the integrity of tissues such as blood vessels, lung, skin and ocular ligaments. A reduction in fibrillin is seen in tissues in vascular ageing, chronic obstructive pulmonary disease, skin ageing and UV induced skin damage, and age-related vision deterioration. Most mutations in fibrillin cause Marfan syndrome, a genetic disease characterised by overgrowth of the long bones and other skeletal abnormalities with cardiovascular and eye defects. However, mutations in fibrillin and fibrillin-binding proteins can also cause short-stature pathologies. All of these diseases have been linked to dysregulated growth factor signalling which forms a major functional role for fibrillin.

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LOXL1-associated Candidate Epithelial Pathomechanisms in Exfoliation Glaucoma

Cited by 11 publications

References 22 publications

Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses

Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors

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