GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

Nair, K. Saidas; Srivastava, Chitrangda; Brown, Robert V.; Koli, Swanand; Choquet, Hélène; Kang, Hong Soon; Kuo, Yien–Ming; Grimm, Sara A.; Sutherland, Caleb; Badea, Alexandra; Johnson, G. Allan; Yin, Zhang; Yin, Jie; Okamoto, Kazushi; Clark, Graham; Borrás, Terete; Zode, Gulab; Kizhatil, Krishnakumar; Chakrabarti, Subhabrata; John, Simon W. M.; Jorgenson, Eric; Jetten, Anton M.

doi:10.1038/s41467-021-25181-7

Cited by 23 publications

(18 citation statements)

References 96 publications

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“…Gd-MRI was applied to analyze aqueous humor dynamics as previously described ( Ho et al, 2014 ; Nair et al, 2021 ). All MRI analyses were performed using a Pharmascan 7T (BRUKER).…”

Section: Methodsmentioning

confidence: 99%

Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells

Yan

Liu

et al. 2022

Front. Cell Dev. Biol.

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Trabecular meshwork dysfunction is the main cause of primary open angle glaucoma (POAG) associated with elevated intraocular pressure (IOP). Mutant myocilin causes glaucoma mainly via elevating IOP. Previously we have found that accumulated Asn 450 Tyr (N450Y) mutant myocilin impairs human trabecular meshwork (TM) cells by inducing chronic endoplasmic reticulum (ER) stress response in vitro. However, it is unclear how ER stress leads to TM damage and whether N450Y myocilin mutation is associated with POAG in vivo. Here we found that N450Y mutant myocilin induces autophagy, which worsens cell viability, whereas inhibition of autophagy increases viability and decreases cell death in human TM cells. Furthermore, we construct a transgenic mouse model of N450Y myocilin mutation (Tg-MYOCN450Y) and Tg-MYOCN450Y mice exhibiting glaucoma phenotypes: IOP elevation, retinal ganglion cell loss and visual impairment. Consistent with our published in vitro studies, mutant myocilin fails to secrete into aqueous humor, causes ER stress and actives autophagy in Tg-MYOCN450Y mice, and aqueous humor dynamics are altered in Tg-MYOCN450Y mice. In summary, our studies demonstrate that activation of autophagy is correlated with pathogenesis of POAG.

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“…Gd-MRI was applied to analyze aqueous humor dynamics as previously described ( Ho et al, 2014 ; Nair et al, 2021 ). All MRI analyses were performed using a Pharmascan 7T (BRUKER).…”

Section: Methodsmentioning

confidence: 99%

Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells

Yan

Liu

et al. 2022

Front. Cell Dev. Biol.

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“…Aqueous humor (AH) homeostasis is critical for maintaining normal intraocular pressure ( 91 ). By contrast, increased obstruction or resistance to the atrial fluid flow through the trabecular meshwork (TM) causes increased intraocular pressure and is a major risk element for primary intraocular pressure elevation ( 92 ). In a previous study, in human TM (HTM) cells, Hic-5 expression was limited to the focal adhesion of HTM cells, as well as throughout the TM and AH efflux pathways of the Schlemm's canal; the administration of recombinant Hic-5 was found to result in the redistribution of actin stress fibers, focal adhesion and αv integrins in the focal adhesion, along with an increase in a-SMA, and increased collagen-1 expression, whereas the knockdown of Hic-5 reversed these effects.…”

Section: Hic-5 and Other Diseasesmentioning

confidence: 99%

Physiological and pathological roles of Hic‑5 in several organs (Review)

Yao

Tu²,

Yang

et al. 2022

Int J Mol Med

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Integrins allow cells to adhere to the extracellular matrix and promote the recruitment of other integrins, resulting in the formation of focal adhesion sites at the binding sites. Focal adhesion sites play essential roles in the assembly of the cytoskeleton and are vital in shaping the structure of cells. They also play other regulatory roles by influencing numerous biological functions, such as cell proliferation and apoptosis. Hydrogen peroxide-inducible clone 5 (Hic-5) is a member of the Paxillin family of proteins and is an adhesive plaque scaffolding protein. Its expression can be detected in both vascular and smooth muscle cells. Thus, it plays an essential role in vascular remodeling, as well as in fibrotic diseases. Hic-5 functions as a coactivator of steroid receptors, thus playing a role in steroid hormone-dependent diseases. It also plays a vital role in the invasive metastasis of various types of cancer. Moreover, several studies have demonstrated that Hic-5 plays a critical role in transcriptional regulation, as well as in numerous signaling pathways. Therefore, the inhibition of the functions of Hic-5 may prevent the development or halt the progression of several diseases. Its use as a therapeutic target in future investigations may thus aid in the treatment of several diseases, including various types of cancer. The present review article focused on the expression and functions of Hic-5 in different organs, with the aim of highlighting novel possibilities for future research.

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“…ANGPT1 and SVEP1 have also been investigated and are considered promising candidate molecules for novel glaucoma therapies ( Thomson et al, 2021 ). GLIS1 was shown to be associated with glaucoma by regulating and maintaining trabecular meshwork function ( Nair et al, 2021 ). Although there is an overlap in the epidemiology and pathophysiology between AD and glaucoma, whether the shared features of the two diseases could be explained genetically, that is, whether they are genetically related, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Shared genetic architecture between the two neurodegenerative diseases: Alzheimer’s disease and glaucoma

Zheng

Liu²,

Zhang³

et al. 2022

Front. Aging Neurosci.

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BackgroundConsidered as the representatives of neurodegenerative diseases, Alzheimer’s disease (AD) and glaucoma are complex progressive neuropathies affected by both genetic and environmental risk factors and cause irreversible damages. Current research indicates that there are common features between AD and glaucoma in terms of epidemiology and pathophysiology. However, the understandings and explanations of their comorbidity and potential genetic overlaps are still limited and insufficient.MethodGenetic pleiotropy analysis was performed using large genome-wide association studies summary statistics of AD and glaucoma, with an independent cohort of glaucoma for replication. Conditional and conjunctional false discovery rate methods were applied to identify the shared loci. Biological function and network analysis, as well as the expression level analysis were performed to investigate the significance of the shared genes.ResultsA significant positive genetic correlation between AD and glaucoma was identified, indicating that there were significant polygenetic overlaps. Forty-nine shared loci were identified and mapped to 11 shared protein-coding genes. Functional genomic analyses of the shared genes indicate their modulation of critical physiological processes in human cells, including those occurring in the mitochondria, nucleus, and cellular membranes. Most of the shared genes indicated a potential modulation of metabolic processes in human cells and tissues. Furthermore, human protein–protein interaction network analyses revealed that some of the shared genes, especially MTCH2, NDUFS3, and PTPMT1, as well as SPI1 and MYBPC3, may function concordantly. The modulation of their expressions may be related to metabolic dysfunction and pathogenic processes.ConclusionOur study identified a shared genetic architecture between AD and glaucoma, which may explain their shared features in epidemiology and pathophysiology. The potential involvement of these shared genes in molecular and cellular processes reflects the “inter-organ crosstalk” between AD and glaucoma. These results may serve as a genetic basis for the development of innovative and effective therapeutics for AD, glaucoma, and other neurodegenerative diseases.

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GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

Cited by 23 publications

References 96 publications

Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells

Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells

Physiological and pathological roles of Hic‑5 in several organs (Review)

Shared genetic architecture between the two neurodegenerative diseases: Alzheimer’s disease and glaucoma

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