Unfolded protein response is activated in aged retinas

Abstract

An unfolded protein response (UPR) in addition to oxidative stress and the inflammatory response is known to be activated in age-related ocular disorders, such as macular degeneration, diabetic retinopathy, glaucoma, and cataracts. Therefore, we aimed to investigate whether healthy aged retinas display UPR hallmarks, in order to establish a baseline for the activated UPR markers for age-related ocular diseases. Using western blotting, we determined that the hallmarks of the UPR PERK arm, phosphorylated (p) eIF2a, ATF4, and GADD34, were significantly altered in aged vs. young rat retinas. The cleaved pATF6 (50) and CHOP proteins were dramatically upregulated in the aged rodent retinas, indicating the activation of the ATF6 UPR arm. The UPR activation was associated with a drop in rhodopsin expression and in the NRF2 and HO1 levels, suggesting a decline in the anti-oxidant defense in aged retinas. Moreover, we observed down-regulation of anti-inflammatory IL-10 and IL-13 and upregulation of pro-inflammatory RANTES in the healthy aged retinas, as measured using the Bio-plex assay. Our results suggest that cellular homeostasis in normal aged retinas is compromised, resulting in the concomitant activation of the UPR, oxidative stress, and inflammatory signaling. This knowledge brings us closer to understanding the cellular mechanisms of the age-related retinopathies and ocular disorders characterized by an ongoing UPR, and highlight the UPR signaling molecules that should be validated as potential therapeutic targets.

Endoplasmic reticulum proteostasis impairment in aging

“…Of interest, gene expression profile studies demonstrated that UPR‐target genes are one of the most affected pathways in bone marrow during aging (Kannan et al ., ). At the level of the central nervous system, phosphorylation of CHOP, ATF6, GADD34, ATF4, and eIF2α are also upregulated in the retina of aged rats (Lenox et al ., ).…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…Several studies have revealed that the age-related tissue atrophy and degeneration are associated with a decline in the amounts of many UPR-related transducers and chaperones, whereas the expression of ER stress linked CHOP was significantly increased with aging, e.g., in mouse cerebral cortex [48] and adipose tissues [49] as well as in the skeletal muscles [50], liver [51], and retina [52] of rats. CHOP is not only associated with apoptosis, it performs many immune and metabolic responses as well as having effects on adipocyte and osteoblast differentiation [53].…”

Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases

“…There are several limitations that should be addressed. For example, the unfolded protein response not only occurs neurodegenerative disorders, but is also activated as a part of the normal aging process, which is marked by an increase in oxidative stress and the pro-inflammatory state (Lenox et al, 2015). Jackson et al hypothesized that aging results in disturbance of the visual cycle responsible for rhodopsin regeneration.…”