GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice.
Irina V SaltykovaAssylbek ZhylkibayevOleg S GorbatyukMarina S GorbatyukPublished in: International journal of molecular sciences (2022)
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 rd 16 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.
Keyphrases
- cell death
- high fat diet induced
- optical coherence tomography
- poor prognosis
- diabetic retinopathy
- dna damage
- binding protein
- drug delivery
- oxidative stress
- cell cycle arrest
- metabolic syndrome
- cell proliferation
- optic nerve
- signaling pathway
- inflammatory response
- long non coding rna
- insulin resistance
- type diabetes
- adipose tissue
- radiofrequency ablation
- skeletal muscle
- atrial fibrillation
- deep learning
- electronic health record
- replacement therapy
- protein protein
- data analysis
- metal organic framework