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WGC-2021

Editors Selection IGR 21-4

Basic Science: Endoplasmic Reticulum Protein Load and Glaucoma

Katie Bollinger
Barbara Mysona

Comment by Katie Bollinger & Barbara Mysona on:

90872 ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load, Kasetti RB; Patel PD; Maddineni P et al., Nature communications, 2020; 11: 5594


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Recent studies indicate that chronic ER stress, which develops upon intracellular accumulation of unfolded and misfolded proteins, plays a significant role in the pathophysiology of glaucoma. However, the molecular mechanisms that underlie ER stress-mediated trabecular meshwork (TM) dysfunction and lead to increased intraocular pressure are not well understood. Activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) are factors known to play a role in several ER stress-associated diseases. ATF4 and CHOP induce the growth arrest and DNA damage-inducible protein (GADD34), which promotes dephosphorylation of elF2&alfa;, leading to increased protein synthesis. Recent studies also indicate that ATF4, CHOP and GADD34 are induced in post-mortem TM tissues from POAG donor eyes.

This work uses a thorough and multifaceted approach to examine the role of ATF4 in the chronic ER stress induced ATF4-CHOP-GADD34 pathway within the TM in human and mouse glaucoma. The authors begin by demonstrating that ATF4, CHOP, and GADD34 are elevated in primary TM cells and tissue from glaucomatous donor eyes. They also show that ATF4 and CHOP are elevated in a mouse model of dexamethasone-induced ocular hypertension. Next, the authors use adenoviral and lentiviral-mediated expression of ATF4 in mouse (C57BL6J) eyes, in GTM3 cell lines, and in primary human TM cells to dissect the molecular mechanisms by which ATF4 leads to glaucoma. They find that increased expression of ATF4 in murine TM leads to significant and sustained IOP elevation that results in glaucomatous neurodegeneration. They use CHOP-/- mice to show that CHOP is required for ATF4-induced IOP elevation. To further assess how ATF4 leads to IOP elevation and TM damage, the authors examine ER stress markers, protein synthesis levels, and ER client protein load in Ad.ATF4-transduced GTM3 cells, primary human TM cells and mouse TM tissues. Results indicated that ATF4 increases protein synthesis and ER client protein load in trabecular meshwork. Further experiments also show that ATF4 expression leads to ER-stress-induced cell death within the TM. A particularly exciting aspect of this work shows that suppression of the ATF4-CHOP pathway using either pharmacological or genetic inhibition reduces elevated IOP in Dexamethasone-treated or mutant myocilin ocular hypertensive mice.

The authors have done an excellent job of using a variety of techniques, models and approaches to demonstrate the important role of the ATF4-CHOP-GADD34 pathway in the TM, particularly the role of ATF4 expression in promoting protein synthesis and ER client protein load. One intriguing observation from this work is that ATF4-CHOP interactions may be cell-type specific; TM tissue may require ATF4-CHOP interactions to regulate ER protein client load, whereas other tissues may not.

ATF4-CHOP-GADD34 signaling pathway plays a key pathological role in TM dysfunction and IOP elevation

An interesting question is whether ATF4-CHOP mechanisms are important at the optic nerve head, another region critically affected in glaucoma. In summary these studies indicate that the ATF4-CHOP-GADD34 signaling pathway plays a key pathological role in TM dysfunction and IOP elevation. Inhibition of this pathway offers a potential therapeutic target for slowing glaucomatous progression.

References

  1. Pitale PM, Gorbatyuk O, Gorbatyuk M. Neurodegeneration: keeping ATF4 on a tight leash. Front Cell Neurosci. 2017;11:410.
  2. Kasetti RB, Maddinene P, Millar JC, Clark AF, Zode GS. Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork. Sci Rep. 2017;7:14951.
  3. Kroeger H, Chiang WC, Felden J, Nguyen A, Lin JH. ER stress and unfolded protein response in ocular health and disease. FEBSJ. 2019;286:399-412.
  4. Peters JC, Bhattacharya S, Clark AF, Zode GS. Increased endoplasmic reticulum stress in human glaucomatous trabecular meshwork cells and tissues. Invest Ophthalmol Vis Sci. 2015;56:3860-3868.


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