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Editors Selection IGR 17-4

Basic Science: Proteomics

Comment by Derek Welsbie on:

Rodent models of ocular hypertension have been useful in elucidating the molecular pathways responsible for retinal ganglion cell (RGC) axon degeneration and cell death. In most cases, however, the relevance of these studies to human pathophysiology has yet to be determined. Moreover, the nature of the initial injury to RGC axons is even less clearly understood. Thus, in order to gain insight into the mechanism by which elevated intraocular pressure injures human RGCs, Yang et al. used a proteomic approach and compared six retinas isolated from patients with longstanding ocular hypertension (without any evidence of glaucomatous optic neuropathy) to six retinas isolated from normotensive age- and gender-matched controls. Protein was extracted from each of the matched retinas, differentially labeled with either ¹⁶O (normal oxygen) or ¹⁸O (heavy oxygen), and then each pair was analyzed by liquid chromatography mass spectrometry (LC-MS). Six pairwise comparisons were then made, looking for proteins whose expression consistently changed in the setting of ocular hypertension. The results showed that certain signaling pathways had a clear overrepresentation of protein level changes, including including those that regulate elongation initiation factor 2 (eIF2), eIF4, mammalian target of rapamycin (mTOR), clathrin-mediated endocytosis, protein ubiquitination and mitochondrial function. Somewhat less significant associations were found with mitogen-activated protein kinases and proteins that mediate signaling in response to endoplasmic reticulum (ER) stress, calcium overload, oxidative stress and endothelin-1, all of which have been shown to play a role in RGC injury in rodents. While it is important to avoid over-interpreting the results, there does seem to be a suggestion that ocular hypertension causes a mismatch in energy supply and demand. Since the retinas were obtained from patients without obvious RGC loss, future studies will almost certainly examine how the spectrum of changes would differ if active RGC loss were occurring.

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