Retinal proteomics of experimental glaucoma model reveal intraocular pressure-induced mediators of neurodegenerative changes

Mehdi Mirzaei*, Vivek K. Gupta, Nitin Chitranshi, Liting Deng, Kanishka Pushpitha, Mojdeh Abbasi, Joel M. Chick, Rashi Rajput, Yunqi Wu, Matthew J. McKay, Ghasem H. Salekdeh, Veer B. Gupta, Paul A. Haynes, Stuart L. Graham

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Current evidence suggests that exposure to chronically induced intraocular pressure (IOP) leads to neurodegenerative changes in the inner retina. This study aimed to determine retinal proteomic alterations in a rat model of glaucoma and compared findings with human retinal proteomics changes in glaucoma reported previously. We developed an experimental glaucoma rat model by subjecting the rats to increased IOP (9.3 ± 0.1 vs 20.8 ± 1.6 mm Hg) by weekly microbead injections into the eye (8 weeks). The retinal tissues were harvested from control and glaucomatous eyes and protein expression changes analysed using a multiplexed quantitative proteomics approach (TMT-MS3). Immunofluorescence was performed for selected protein markers for data validation. Our study identified 4304 proteins in the rat retinas. Out of these, 139 proteins were downregulated (≤0.83) while the expression of 109 proteins was upregulated (≥1.2-fold change) under glaucoma conditions (P ≤.05). Computational analysis revealed reduced expression of proteins associated with glutathione metabolism, mitochondrial dysfunction/oxidative phosphorylation, cytoskeleton, and actin filament organisation, along with increased expression of proteins in coagulation cascade, apoptosis, oxidative stress, and RNA processing. Further functional network analysis highlighted the differential modulation of nuclear receptor signalling, cellular survival, protein synthesis, transport, and cellular assembly pathways. Alterations in crystallin family, glutathione metabolism, and mitochondrial dysfunction associated proteins shared similarities between the animal model of glaucoma and the human disease condition. In contrast, the activation of the classical complement pathway and upregulation of cholesterol transport proteins were exclusive to human glaucoma. These findings provide insights into the neurodegenerative mechanisms that are specifically affected in the retina in response to chronically elevated IOP.

Original languageEnglish
Pages (from-to)4931-4944
Number of pages14
JournalJournal of Cellular Biochemistry
Volume121
Issue number12
Early online date21 Jul 2020
DOIs
Publication statusPublished - Dec 2020

Keywords

  • glaucoma
  • neurodegeneration
  • proteomics
  • retina

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