Pharmacological Modulation of the Retinal Unfolded Protein Response in Bardet-Biedl Syndrome Reduces Apoptosis and Preserves Light Detection Ability

Mockel, Anaïs; Obringer, Cathy; Hakvoort, Theodorus B. M.; Seeliger, Mathias W.; Lamers, Wouter H.; Stoetzel, Corinne; Dollfus, Hélène; Marion, Vincent

doi:10.1074/jbc.m112.386821

Cited by 44 publications

(64 citation statements)

References 60 publications

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“…Signaling through the UPR is largely mediated by activation of the IRE1, PERK, and AFT6 pathways. However, in cases in which the stress signals are prolonged or too severe, the ER may trigger cell death through activation of the caspase-12 pathway [6].…”

Section: Discussionmentioning

confidence: 99%

“…Chronic or severe activation of the UPR promotes the induction of caspase-12-mediated apoptosis [6]. Increasing evidence indicates that persistent oxidative stress results in apoptosis via the induction of ER stress.…”

Section: And Qian Yangmentioning

confidence: 99%

“…However, persistent ER stress can lead to cell death through activation of the caspase-12-mediated apoptosis pathway [6]. Thus, we next tested whether salidroside treatment specifically reduces ER stress-induced cell death.…”

Section: Salidroside Attenuates Er Stress-related Cell Death In Sn474mentioning

confidence: 99%

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Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress

et al. 2016

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Parkinson's disease (PD) is a neurodegenerative disease characterized by a persistent decline of dopaminergic (DA) neurons in the substantia nigra pars compacta. Despite its frequency, effective therapeutic strategies that halt the neurodegenerative processes are lacking, reinforcing the need to better understand the molecular drivers of this disease. Importantly, increasing evidence suggests that the endoplasmic reticulum (ER) stress-induced unfolded protein response is likely involved in DA neuronal death. Salidroside, a major compound isolated from Rhodiola rosea L., possesses potent antioxidative stress properties and protects against DA neuronal death. However, the underlying mechanisms are not well understood. In the present study, we demonstrate that salidroside prevents 6-hydroxydopamine (6-OHDA)-induced cytotoxicity by attenuating ER stress. Furthermore, treatment of a DA neuronal cell line (SN4741) and primary cortical neurons with salidroside significantly reduced neurotoxin-induced increases in cytoplasmic reactive oxygen species and calcium, both of which cause ER stress, and cleaved caspase-12, which is responsible for ER stress-induced cell death. Together, these results suggest that salidroside protects SN4741 cells and primary cortical neurons from 6-OHDA-induced neurotoxicity by attenuating ER stress. This provides a rationale for the investigation of salidroside as a potential therapeutic agent in animal models of PD.

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Section: Discussionmentioning

confidence: 99%

Section: And Qian Yangmentioning

confidence: 99%

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Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress

et al. 2016

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“…In addition to constitutive G-protein signaling, there are naturally occurring rhodopsin mutations in human patients afflicted with autosomal dominant retinitis pigmentosa that have a tendency to misfold, and it has been demonstrated that these mutants also induce the UPR (32,36,54). Therefore, strategies to control ER stress, either by overexpression of GRP78 (55) or application of small molecules that modulate UPR (41,56,57), may be effective in the treatment of these types of retinal degenerative diseases.…”

Section: Our Findings On Arr1mentioning

confidence: 99%

Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

Chen

2014

Journal of Biological Chemistry

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Background: Excessive light exposure and genetic mutations that act as "equivalent light" cause photoreceptor cell death. Results: Prolonged transducin signaling, but not channel closure, induces endoplasmic reticulum stress. Conclusion: Induction of UPR is a distinct cell death pathway caused by transducin signaling. Significance: Manipulation of UPR may prolong photoreceptor cell survival in transducin-induced retinal light damage.

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“…For example, the thoroughly studied P23H mutation in rhodopsin (a single amino acid substitution of proline at position 23 for histidine), frequently encountered in retinitis pigmentosa patients (2,3), was shown to cause rhodopsin misfolding and endoplasmic reticulum (ER) accumulation (4,5), ultimately resulting in an unfolded protein response and cell death (6,7). Protein misfolding is considered a therapeutic target in the ongoing clinical trial in which patients with retinitis pigmentosa are treated with valproic acid (http:// clinicaltrials.gov/ct2/show/study/NCT01233609), the substance suggested to act as a pharmacological chaperone for unfolded proteins (8,9).…”

mentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Inherited retinal degenerations, caused by mutations in over 100 individual genes, affect approximately 2 million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors. This places an increased burden on the protein folding and degradation machinery, which may trigger cell death. We analyzed how these cellular functions are affected in degenerating rods of the transducin γ-subunit (Gγ 1 ) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ 1 ), which cannot fold without Gγ 1 and undergoes intracellular proteolysis instead of forming a transducin βγ-subunit complex. Our data revealed that the most critical pathobiological factor leading to photoreceptor cell death in these animals is insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein. A decrease in the Gβ 1 production in Gγ 1 knockout rods resulted in a significant reduction in proteasomal overload and caused a striking reversal of photoreceptor degeneration. We further demonstrated that a similar proteasomal overload takes place in photoreceptors of other mutant mice where retinal degeneration has been ascribed to protein mistargeting or misfolding, but not in mice whose photoreceptor degenerate as a result of abnormal phototransduction. These results establish the prominence of proteasomal insufficiency across multiple degenerative diseases of the retina, thereby positioning proteasomes as a promising therapeutic target for treating these debilitating conditions. neurodegenerative diseases | protein degradation

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Pharmacological Modulation of the Retinal Unfolded Protein Response in Bardet-Biedl Syndrome Reduces Apoptosis and Preserves Light Detection Ability

Cited by 44 publications

References 60 publications

Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress

Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress

Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

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