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Endoplasmic reticulum stress: New insights into the pathogenesis and treatment of retinal degenerative diseases.

ABSTRACT: Physiological equilibrium in the retina depends on coordinated work between rod and cone photoreceptors and can be compromised by the expression of mutant proteins leading to inherited retinal degeneration (IRD). IRD is a diverse group of retinal dystrophies with multifaceted molecular mechanisms that are not fully understood. In this review, we focus on the contribution of chronically activated unfolded protein response (UPR) to inherited retinal pathogenesis, placing special emphasis on studies employing genetically modified animal models. As constitutively active UPR in degenerating retinas may activate pro-apoptotic programs associated with oxidative stress, pro-inflammatory signaling, dysfunctional autophagy, free cytosolic Ca²⁺ overload, and altered protein synthesis rate in the retina, we focus on the regulatory mechanisms of translational attenuation and approaches to overcoming translational attenuation in degenerating retinas. We also discuss current research on the role of the UPR mediator PERK and its downstream targets in degenerating retinas and highlight the therapeutic benefits of reprogramming PERK signaling in preclinical animal models of IRD. Finally, we describe pharmacological approaches targeting UPR in ocular diseases and consider their potential applications to IRD.

SUBMITTER: Gorbatyuk MS

PROVIDER: S-EPMC7541398 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases.

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Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons.

Project description:PURPOSE:To investigate the mechanism of ? receptor 1 (?R1) neuroprotection in retinal neurons. METHODS:Oxidative stress, which is implicated in diabetic retinopathy, was induced in mouse primary ganglion cells (GCs) and RGC-5 cells, and the effect of the ?R1 ligand (+)-pentazocine on pro- and anti-apoptotic and endoplasmic reticulum (ER) stress gene expression was examined. Binding of ?R1 to BiP, an ER chaperone protein, and ?R1 phosphorylation status were examined by immunoprecipitation. Retinas were harvested from Ins2Akita/+ diabetic mice treated with (+)-pentazocine, and the expression of ER stress genes and of the retinal transcriptome was evaluated. RESULTS:Oxidative stress induced the death of primary GCs and RGC-5 cells. The effect was decreased by the application of (+)-pentazocine. Stress increased ?R1 binding to BiP and enhanced ?R1 phosphorylation in RGC-5 cells. BiP binding was prevented, and ?R1 phosphorylation decreased in the presence of (+)-pentazocine. The ER stress proteins PERK, ATF4, ATF6, IRE1?, and CHOP were upregulated in RGC-5 cells during oxidative stress, but decreased in the presence of (+)-pentazocine. A similar phenomenon was observed in retinas of Ins2Akita/+ diabetic mice. Retinal transcriptome analysis of Ins2Akita/+ mice compared with wild-type revealed differential expression of the genes critically involved in oxidative stress, differentiation, and cell death. The expression profile of those genes was reversed when the Ins2Akita/+ mice were treated with (+)-pentazocine. CONCLUSIONS:In retinal neurons, the molecular chaperone ?R1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating ?R1 from BiP. As stress in retinal cells increases, phosphorylation of ?R1 is increased, which is attenuated when agonists bind to the receptor.

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Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration.

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases.

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