July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Increased expression of ATF4 in trabecular meshwork elevates IOP and leads to glaucomatous neurodegeneration by increasing secretory protein load of the endoplasmic reticulum
Author Affiliations & Notes
  • Gulab Zode
    Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, Fort Worth, Texas, United States
  • Ramesh Kasetti
    Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, Fort Worth, Texas, United States
  • Pinkal D Patel
    Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, Fort Worth, Texas, United States
  • prabhavathi maddineni
    Department of Pharmacology and Neuroscience, University of North Texas HSC at Fort Worth, Fort Worth, Texas, United States
  • Val Sheffield
    University of Iowa, Iowa city, Iowa, United States
  • Footnotes
    Commercial Relationships   Gulab Zode, None; Ramesh Kasetti, None; Pinkal Patel, None; prabhavathi maddineni, None; Val Sheffield, None
  • Footnotes
    Support  National Eye Institute (EY026177 and EY028616) and Bright Focus Glaucoma Foundation.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5215. doi:
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      Gulab Zode, Ramesh Kasetti, Pinkal D Patel, prabhavathi maddineni, Val Sheffield; Increased expression of ATF4 in trabecular meshwork elevates IOP and leads to glaucomatous neurodegeneration by increasing secretory protein load of the endoplasmic reticulum. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5215.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Elevated IOP due to damage to the trabecular meshwork (TM) is associated with primary open angle glaucoma (POAG). We have previously shown that chronic endoplasmic reticulum (ER) stress is associated with glaucomatous TM damage and IOP elevation. However, it is not understood how chronic ER stress leads to TM dysfunction and IOP elevation. Here, we explored the pathological roles of chronic ER stress-induced activating transcription factor 4 (ATF4) in TM dysfunction and IOP elevation.

Methods : ATF4 levels were examined in TM of mouse model of glucocorticoid (GC)-induced glaucoma and in human TM tissues. C57 mice were injected intravitreally with Ad5 or lentiviruses expressing ATF4 and CHOP and glaucoma phenotype was examined. Human primary TM or GTM3 cells were transduced with Ad5 ATF4 or CHOP and ECM and ER stress was examined using Western blot and immunostaining.

Results : ATF4 is induced in the TM of POAG human donor eyes and mouse models of glaucoma. Adenoviral expression of ATF4 in mouse TM reduced aqueous humor outflow facility and elevated IOP significantly. Lentivirus expressing ATF4 led to sustained IOP elevation without any ocular toxicity. Lentiviral ATF4-induced IOP elevation for 10 weeks resulted in significant loss of RGCs (21%) and optic nerve degeneration. Interestingly, we observed that Ad5 expression of downstream ER stress transcriptional factor, CHOP did not elevate IOP significantly in mice. ATF4 interacted with CHOP in TM cells and expression of ATF4 did not elevate IOP in CHOP knockout mice, suggesting that ATF4 interaction with CHOP is essential in ATF4-induced IOP elevation. Also, ATF4 induced TM dysfunction and cell death in vitro and in vivo models in a CHOP dependent manner. Strikingly, genetic depletion of ATF4 via genome editing or pharmacological inhibition via treatment with ISRIB rescued ocular hypertension in mouse models of glaucoma. We further show that ATF4 induces de novo protein synthesis of secretory proteins, causing increased secretory load on ER of TM cells.

Conclusions : These data indicate that ATF4 leads to TM cell death/dysfunction, elevating IOP and inhibition of ATF4-CHOP pathway be a novel disease intervention strategy for treating glaucoma.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Expression of ATF4 leads to IOP elevation in C57 mice.

Expression of ATF4 leads to IOP elevation in C57 mice.

 

ATF4-induced IOP elevation leads to RGC loss after 10-weeks of injection.

ATF4-induced IOP elevation leads to RGC loss after 10-weeks of injection.

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