Delineating the role of eIF2α in retinal degeneration

Starr, Christopher R.; Gorbatyuk, Marina S.

doi:10.1038/s41419-019-1641-y

Cited by 8 publications

(10 citation statements)

References 42 publications

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“…Although some literature suggests that PERK pathway stimulation via interventions like Salubrinal can be neuroprotective via prolonged increases in p-eIF2α (Starr and Gorbatyuk, 2019;Athanasiou et al, 2017) or nrf2 (Comitato et al, 2020), we do not show similar protection in this model. Nor do we show protection when decreasing activation of this pathway, as others have reported with both ISRIB (Chou et al, 2017;Wenzhu Zhou et al, 2023) and other interventions against downstream proteins like ATF4 or CHOP in models of TBI (Hu et al, 2019;Neill and Masson, 2023;Pitale et al, 2017;Song et al, 2008).…”

Section: Discussioncontrasting

confidence: 99%

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Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Hetzer,

Bellary,

Torrens

et al. 2024

Preprint

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Traumatic brain injury (TBI) can induce traumatic axonal injury in the optic nerve, which is referred to as traumatic optic neuropathy (TON). TON occurs in up to 5% of TBI cases and leads to irreversible visual deficits. TON-induced phosphorylation of eIF2α, a downstream ER stress activator in the PERK pathway presents a potential point for therapeutic intervention. For eIF2α phosphorylation can lead to apoptosis or adaptation to stress. We hypothesized that dephosphorylation, rather than phosphorylation, of eIF2α would lead to reduced apoptosis and improved visual performance and retinal cell survival. Adult male mice were injected with Salubrinal (increases p-eIF2α) or ISRIB (decreases p-eIF2α) 60 minutes post-injury. Contrary to literature, both drugs hindered control animal visual function with minimal improvements in injured mice. Additionally, differences in eIF2α phosphorylation, antioxidant responses, and protein folding chaperones were different when examining protein expression between the retina and its axons in the optic nerve. These results reveal important compartmentalized ER stress responses to axon injury and suggest that interventions in the PERK pathway may alter necessary homeostatic regulation of the UPR in the retina.

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Section: Discussioncontrasting

confidence: 99%

“…For example, it was found that targeting p-eIF2α, both by systemic GADD34 knockout and photoreceptor specific PERK knock out, in a model of inherited retinal degenerative disease was not protective. Instead, retinal cells might be required to activate alternative pathways for protein synthesis control (Starr and Gorbatyuk, 2019).…”

Section: Discussionmentioning

confidence: 99%

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Hetzer,

Bellary,

Torrens

et al. 2024

Preprint

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“…ER stress is a defensive response to a host of stimulants, but it can evolve to encompass cell injury [35]. PERK/eIF2α is one of the main pathways for ER stress-mediated apoptosis [36]. However, recent studies have shown that increasing eIF2α phosphorylation protected injured cells [37].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury

Tang

Chen

et al. 2020

BioMed Research International

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Objectives. Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.

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“…These mice expressed truncated CEP290, manifested chronic ISR activation, and developed severe RD rapidly, thus modeling Leber congenital amaurosis 10 and RP in humans. We demonstrated that GADD34-mediated manipulation with the p-eIF2α level in rd16 photoreceptors does not modify the translation rate and has no major impact on retinal function in mice with ciliopathies, although GADD34 ablation slowed down the rate of apoptotic cell death [2]. This is why we have become interested in understanding whether the GADD34-mediated elevation of p-eIF2α in retinas degenerating at a slower pace alters the progression of retinal dystrophy in mice.…”

Section: Introductionmentioning

confidence: 98%

GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice

Saltykova

Zhylkibayev

Gorbatyuk

et al. 2022

IJMS

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The UPR is sustainably activated in degenerating retinas, leading to translational inhibition via p-eIF2α. Recent findings have demonstrated that ablation of growth arrest and DNA damage-inducible protein 34 (GADD34), a protein phosphatase 1 regulatory subunit permitting translational machinery operation through p-eIF2α elevation, does not impact the rate of translation in fast-degenerating rd16 mice. The current study aimed to validate whether P23H RHO mice degenerating at a slower pace manifest translational attenuation and whether GADD34 ablation impacts the rate of retinal degeneration via further suppression of retinal protein synthesis and apoptotic cell death. For this study, mice were examined with ERG and histological analyses. The molecular assessment was conducted in the naïve and LPS-challenged mice using Western blot and qRT-PCR analyses. Thus, this study demonstrates that the P23H RHO retinas manifest translational attenuation. However, GADD34 ablation resulted in a more prominent p-eIF2a increase without impacting the translation rate. GADD34 deficiency also led to a reduction in scotopic ERG amplitudes and an increased number of TUNEL-positive cells. Molecular analysis revealed that GADD34 deficiency reduces the expression of p-STAT3 and Il-6 while increasing the expression of Tnfa. Overall, the data indicate that GADD34 plays a multifunctional role. Under chronic UPR activation, GADD34 acts as a feedback player, dephosphorylating p-eIF2a, although this role does not seem to be critical. Additionally, GADD34 controls cytokine expression and STAT3 activation. Perhaps these molecular events are particularly important in controlling the pace of retinal degeneration.

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Delineating the role of eIF2α in retinal degeneration

Cited by 8 publications

References 42 publications

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury

GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice

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