Correlation of ER stress and retinal degeneration in tubby mice

Cai, Xue; Chen, Lijuan; McGinnis, James F.

doi:10.1016/j.exer.2015.08.022

Cited by 9 publications

(9 citation statements)

References 56 publications

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“…also observed induction of key ER-UPR stress markers in the retinas of the Tubby mice. Their data also demonstrated that ER stress triggers apoptosis via down-regulation of Bcl2, up-regulation of CHOP (similar to our report) and the activation of NF-кB signaling [ 67 ].…”

Section: Discussionsupporting

confidence: 89%

“…We are currently pursuing this type of animal model using the CRISPR/Cas9 gene-editing technology to recapitulate patients’ gene dosage and spatiotemporal retinal degeneration [ 65 , 66 ]. Of note, correlation of retinal degeneration and activation of the ER-UPR complex has been reported in the Tubby mice [ 67 ]. Similar to our report, Cai et .…”

Section: Discussionmentioning

confidence: 99%

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Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration

Lobo

Kiser

et al. 2016

PLoS ONE

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Inherited retinal disorders (IRDs) result in severe visual impairments in children and adults. A challenge in the field of retinal degenerations is identifying mechanisms of photoreceptor cell death related to specific genetic mutations. Mutations in the gene TULP1 have been associated with two forms of IRDs, early-onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). TULP1 is a cytoplasmic, membrane-associated protein shown to be involved in transportation of newly synthesized proteins destined for the outer segment compartment of photoreceptor cells; however, how mutant TULP1 causes cell death is not understood. In this study, we provide evidence that common missense mutations in TULP1 express as misfolded protein products that accumulate within the endoplasmic reticulum (ER) causing prolonged ER stress. In an effort to maintain protein homeostasis, photoreceptor cells then activate the unfolded protein response (UPR) complex. Our results indicate that the two major apoptotic arms of the UPR pathway, PERK and IRE1, are activated. Additionally, we show that retinas expressing mutant TULP1 significantly upregulate the expression of CHOP, a UPR signaling protein promoting apoptosis, and undergo photoreceptor cell death. Our study demonstrates that the ER-UPR, a known mechanism of apoptosis secondary to an overwhelming accumulation of misfolded protein, is involved in photoreceptor degeneration caused by missense mutations in TULP1. These observations suggest that modulating the UPR pathways might be a strategy for therapeutic intervention.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration

Lobo

Kiser

et al. 2016

PLoS ONE

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“…The UPR can promote survival under conditions of transient and mild ER stress, or conversely promote cell death by activating downstream apoptosis signaling molecules if ER stress is prolonged and severe. Although cell death under severe ER stress may guard organisms from exposure to improperly folded proteins, many prevalent human diseases—such as diabetes mellitus (Back et al, 2012; Brozzi and Eizirik 2016), acute lung injury (Hu et al, 2015; Li et al, 2015), and retinopathies (Rana et al, 2014; Cai et al, 2015)—may be caused by excessive ER stress–induced cell death (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Dual role for the unfolded protein response in the ovary: adaption and apoptosis

Qiao

2016

Protein &Amp; Cell

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The endoplasmic reticulum (ER) is the principal organelle responsible for several specific cellular functions including synthesis and folding of secretory or membrane proteins, lipid metabolism, and Ca2+ storage. Different physiological as well as pathological stress conditions can, however, perturb ER homeostasis, giving rise to an accumulation of unfolded or misfolded proteins in the ER lumen, a condition termed ER stress. To deal with an increased folding demand, cells activate the unfolded protein response (UPR), which is initially protective but can become detrimental if ER stress is severe and prolonged. Accumulating evidence demonstrates a link between the UPR and ovarian development and function, including follicular growth and maturation, follicular atresia, and corpus luteum biogenesis. Additionally, ER stress and the UPR may also play an important role in the ovary under pathological conditions. Understanding the molecular mechanisms related to the dual role of unfolded protein response in the ovarian physiology and pathology may reveal the pathogenesis of some reproductive endocrine diseases and provide a new guidance to improve the assisted reproductive technology. Here we review the current literature and discuss concepts and progress in understanding the UPR, and we also analyze the role of ER stress and the UPR in the ovary.

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“…67 The effect of tunicamycin was the most effective at 2 weeks in a previous study. 68 The limitation of this study is that ER stress inhibitor was not used. Further study is necessary to investigate which specific ER stress inhibitor can reverse the effect of tunicamycin on dry eye syndrome.…”

Section: Discussionmentioning

confidence: 98%

Rapamycin Rescues Endoplasmic Reticulum Stress–Induced Dry Eye Syndrome in Mice

Cho

Hwang

Shin

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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mycin rescues endoplasmic reticulum stress-induced dry eye syndrome in mice. Invest Ophthalmol Vis Sci. 2019;60:1254-1264. https://doi.org/ 10.1167 PURPOSE. To investigate whether rapamycin protects tear production and the ocular surface during endoplasmic reticulum (ER) stress-induced dry eye syndrome in mice. METHODS.Tunicamycin was injected intraperitoneally in BALB/c mice without or with rapamycin (TM or RM5 group). Peritoneal injection of PBS performed in vehicle group. Group without injection served as control. Blinking rate, fluorescein staining score (FSS), and phenol red thread tear production test were measured at 4 days, 1 week, and 2 weeks after treatment. Levels of inflammatory and angiogenic cytokines were measured by ELISA. RESULTS.Blinking rate and FSS were elevated, and tear production was decreased in TM group compared with controls (P < 0.05 for all), which was ameliorated by rapamycin at 1 and 2 weeks. Levels of inflammatory and angiogenic cytokines in the cornea and lacrimal glands were higher in the TM group than controls, and lower in the RM5 group than the TM group at 1 and 2 weeks (P < 0.05 for all).CONCLUSION. Rapamycin protected tear production and the ocular surface against this dry eye syndrome by ameliorating ER stress-induced vascular damage and inflammation of lacrimal glands and the ocular surface.

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Correlation of ER stress and retinal degeneration in tubby mice

Cited by 9 publications

References 56 publications

Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration

Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration

Dual role for the unfolded protein response in the ovary: adaption and apoptosis

Rapamycin Rescues Endoplasmic Reticulum Stress–Induced Dry Eye Syndrome in Mice

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