Dataset Information

Glaucoma Pathogenesis and Neurotrophins: Focus on the Molecular and Genetic Basis for Therapeutic Prospects.

ABSTRACT: BACKGROUND:Retinal ganglion cell (RGC) degeneration is a major feature of glaucoma pathology. Neuroprotective approaches that delay or halt the progression of RGC loss are needed to prevent vision loss which can occur even after conventional medical or surgical treatments to lower intraocular pressure. OBJECTIVE:The aim of this review was to examine the progress in genetics and cellular mechanisms associated with endoplasmic reticulum (ER) stress, RGC dysfunction and cell death pathways in glaucoma. MATERIALS AND METHODS:Here, we review the involvement of neurotrophins like brain derived neurotrophic factor (BDNF) and its high affinity receptor tropomyosin receptor kinase (TrkB) in glaucoma. The role of ER stress markers in human and animal retinas in health and disease conditions is also discussed. Further, we analysed the literature highlighting genetic linkage in the context of primary open angle glaucoma and suggested mechanistic insights into potential therapeutic options relevant to glaucoma management. RESULTS:The literature review of the neurobiology underlying neurotrophin pathways, ER stress and gene associations provide critical insights into association of RGCs death in glaucoma. Alteration in signalling pathway is associated with increased risk of misfolded protein aggregation in ER promoting RGC apoptosis. Several genes that are linked with neurotrophin signalling pathways have been reported to be associated with glaucoma pathology. CONCLUSION:Understanding genetic heterogeneity and involvement of neurotrophin biology in glaucoma could help to understand the complex pathophysiology of glaucoma. Identification of novel molecular targets will be critical for drug development and provide neuroprotection to the RGCs and optic nerve.

SUBMITTER: Chitranshi N

PROVIDER: S-EPMC6120108 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Glaucoma Pathogenesis and Neurotrophins: Focus on the Molecular and Genetic Basis for Therapeutic Prospects.

Chitranshi Nitin N Dheer Yogita Y Abbasi Mojdeh M You Yuyi Y Graham Stuart L SL Gupta Vivek V

Current neuropharmacology 20180101 7

<h4>Background</h4>Retinal ganglion cell (RGC) degeneration is a major feature of glaucoma pathology. Neuroprotective approaches that delay or halt the progression of RGC loss are needed to prevent vision loss which can occur even after conventional medical or surgical treatments to lower intraocular pressure.<h4>Objective</h4>The aim of this review was to examine the progress in genetics and cellular mechanisms associated with endoplasmic reticulum (ER) stress, RGC dysfunction and cell death pa ...[more]

PMID: 29676228

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Project description:CYP1B1 has been implicated in primary congenital glaucoma with autosomal recessive mode of inheritance. Mutations in CYP1B1 have also been reported in primary open angle glaucoma (POAG) cases and suggested to act as a modifier of the disease along with Myocilin (MYOC). Earlier reports suggest that over-expression of myocilin leads to POAG pathogenesis. Taken together, we propose a functional interaction between CYP1B1 and myocilin where 17β estradiol acts as a mediator. Therefore, we hypothesize that 17β estradiol can induce MYOC expression through the putative estrogen responsive elements (EREs) located in its promoter and CYP1B1 could manipulate MYOC expression by metabolizing 17β estradiol to 4-hydroxy estradiol, thus preventing it from binding to MYOC promoter. Hence any mutation in CYP1B1 that reduces its 17β estradiol metabolizing activity might lead to MYOC upregulation, which in turn might play a role in glaucoma pathogenesis. It was observed that 17β estradiol is present in Human Trabecular Meshwork cells (HTM) and Retinal Pigment Epithelial cells (RPE) by immunoflouresence and ELISA. Also, the expression of enzymes related to estrogen biosynthesis pathway was observed in both cell lines by RT-PCR. Subsequent evaluation of the EREs in the MYOC promoter by luciferase assay, with dose and time dependent treatment of 17β estradiol, showed that the EREs are indeed active. This observation was further validated by direct binding of estrogen receptors (ER) on EREs in MYOC promoter and subsequent upregulation in MYOC level in HTM cells on 17β estradiol treatment. Interestingly, CYP1B1 mutants with less than 10% enzymatic activity were found to increase the level of endogenous myocilin in HTM cells. Thus the experimental observations are consistent with our proposed hypothesis that mutant CYP1B1, lacking the 17β estradiol metabolizing activity, can cause MYOC upregulation, which might have a potential implication in glaucoma pathogenesis.

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Dataset Information

Glaucoma Pathogenesis and Neurotrophins: Focus on the Molecular and Genetic Basis for Therapeutic Prospects.

Publications

Glaucoma Pathogenesis and Neurotrophins: Focus on the Molecular and Genetic Basis for Therapeutic Prospects.

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