ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

Lee, Eun-Jin; Chan, Priscilla; Chea, Leon; Kim, Kyle; Kaufman, Randal J.; Lin, Jonathan H.

doi:10.1038/s41598-021-95895-7

Cited by 16 publications

(17 citation statements)

References 71 publications

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“…(60) Alternatively, deficiencies in ATF6 activation induced by environmental insults or aging contribute to retinal degeneration associated with other diseases including retinitis pigmentosa and cone-rod dystrophy. (34, 61) The protection afforded by ATF6 in the retina is likely mediated through its regulation of multiple adaptive genes including the ER chaperones BiP and the neurotrophic factor MANF. (29, 62, 63) Each of these ATF6-regulated genes have been shown to protect photoreceptors and/or Müller glia against diverse types of insults including ER-stress induced apoptosis(34, 64, 65), oxidative stress(66), and age-related retinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

Rosarda

Giles

Harkins‐Perry

et al. 2022

Preprint

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1-Deoxysphingolipids (1-dSLs) are atypical cytotoxic sphingolipids formed through the substitution of alanine for serine in de novo sphingolipid biosynthesis. Accumulation of 1-dSLs has been linked to diseases of the eye such as diabetic retinopathy and Macular Telangiectasia Type 2 (MacTel). However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remains poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define the biological pathways that contribute to toxicity caused by the 1-dSL species, 1-deoxysphinganine (1-dSA), in human retinal organoids. Our results demonstrate that 1-dSA preferentially and differentially activates signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Muller glia within retinal organoids. Using a combination of pharmacologic inhibitors and activators, we define the roles for individual arms of the UPR in 1-dSL-mediated toxicity. We show that sustained PERK signaling through the integrated stress response (ISR) promotes 1-dSL-induced apoptosis in photoreceptors. In contrast, deficiencies in signaling through the ATF6 arm of the UPR contribute to photoreceptor toxicity. These results indicate that imbalanced signaling between the pro-apoptotic PERK/ISR and protective ATF6 arms of the UPR contributes to 1-dSL-induced photoreceptor toxicity. Further, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different signaling arms of the UPR.

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Section: Discussionmentioning

confidence: 99%

“…(29,33) Further, dysregulated signaling through all three UPR pathways is associated with retinal degeneration in diseases such as retinitis pigmentosa. (32)(33)(34)(35) This suggests that the retina, and specifically photoreceptor cells within the retina, are highly sensitive to imbalances in UPR signaling.…”

Section: Introductionmentioning

confidence: 99%

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

Rosarda

Giles

Harkins‐Perry

et al. 2022

Preprint

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“…GO:0001654 (eye development) was mainly enriched with RBP4 and ATF6. RBP4 and ATF6 are signi cantly positively correlated with rod photoreceptors, which in turn affect retinal and visual function [43,44] . GO:0007162 (negative regulation of cell adhesion) was mainly enriched with MDK.…”

Section: Exploring the Regulatory Mechanisms Of High-altitude Adaptiv...mentioning

confidence: 99%

Genetic Diversity and Runs of homozygosity analysis of Hetian Sheep Populations Revealed by Illumina OvineSNP50 BeadChip

Han

Zhou

Zhang

et al. 2022

Preprint

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Background Hetian sheep have a long history, a wide production area and rich genetic resources. Due to the different growing environment and feeding methods, wool, body shape and other traits also have some differences. Hetian sheep can be roughly divided into three groups, but the classification at the genome level is not clear. Results We randomly selected 84 healthy, adult ewes were randomly selected from three different ecological regions in Hetian area of Xinjiang, China. DNA was extracted from Ear tissues using phenol chloroform method to produce Illumina OvineSNP50 BeadChip. The SNP chip data were analyzed by Principal component analysis (PCA), neighbor-joining (NJ) phylogenetic and admixture for the population genetic structure of Hetian sheep, and the degree of population linkage was analyzed based on linkage disequilibrium (LD). Finally, the genetic region selection of Hetian sheep genetic germplasm resource populations in three different ecological environments was obtained by runs of homozygosity (ROH) analysis. The obtained candidate genes were annotated with Oar_v4.0 and enriched by GO and KEGG for analysis.Main screened 31 candidate genes adapting to high altitude environment were obtained in the Mountain type. Among them, Genes related to bone cell generation, differentiation and maintenance of bone homeostasis WNT6, WNT10A, CHSY1, etc. Genes related to tooth and tongue development LEF1, TP63, PRDM16, etc. Hearing and vision-related genes RBP4, ATF6, JAG1, etc. Main screened 22 candidate genes related to economic traits were obtained in the Grass type. Among them, Reproduction-related genes PLA2G4F, ACVR1, ADCY2, etc. Growth-related genes CAPN3, YAP1, FGF9, etc. Conclusions Hetian sheep can be classified into three subtypes at the genomic level: Mountain, Mountain-Grass and Grass types. The Grass type evolved from the Mountain type, and some of the Grass type further evolved into the Mountain-Grass type, and the genetic relationship between the Mountain-Grass type and Grass type was closest. Genetic structure and ROH analysis of Hetian sheep based on genomic microarray technology revealed the Mountain-Grass type strain. We enriched the genetic diversity of Hetian sheep germplasm resources, provided directions for Hetian sheep breed conservation, and found that genes related to multiparous trait exist in Mountain-Grass and Grass types Hetian sheep, which provides ideas for the selection and breeding of multiparous Hetian sheep.

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“…In response to rhodopsin misfolding and ER stress in photoreceptor cells of adRP, a third UPR pathway, mediated by ATF6, is also activated [ 112 ]. Activation of ATF6 upregulates ER chaperones, such as GRP78, to promote protein folding and restore ER homeostasis [ 113 ] [ 99 , 111 ].…”

Section: Introductionmentioning

confidence: 99%

“…In animal models, global ATF6 knockout mice show normal retinal morphology and function at a young age but develop photoreceptor dysfunction with increasing age [ 117 ]. Knockout of ATF6 in a P23H-KI model of RP impairs rhodopsin clearance and accelerates retinal degeneration and functional deficits [ 112 ]. A phenotypic correlation is seen in patients with ATF6 mutation-induced achromatopsia who present foveal hypoplasia, supporting a role of ATF6 in cone development [ 117 , 121 , 123 ].…”

Section: Introductionmentioning

confidence: 99%

Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications

McLaughlin

Medina

Perkins

et al. 2022

Mol Neurodegeneration

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Background The retina, as part of the central nervous system (CNS) with limited capacity for self-reparation and regeneration in mammals, is under cumulative environmental stress due to high-energy demands and rapid protein turnover. These stressors disrupt the cellular protein and metabolic homeostasis, which, if not alleviated, can lead to dysfunction and cell death of retinal neurons. One primary cellular stress response is the highly conserved unfolded protein response (UPR). The UPR acts through three main signaling pathways in an attempt to restore the protein homeostasis in the endoplasmic reticulum (ER) by various means, including but not limited to, reducing protein translation, increasing protein-folding capacity, and promoting misfolded protein degradation. Moreover, recent work has identified a novel function of the UPR in regulation of cellular metabolism and mitochondrial function, disturbance of which contributes to neuronal degeneration and dysfunction. The role of the UPR in retinal neurons during aging and under disease conditions in age-related macular degeneration (AMD), retinitis pigmentosa (RP), glaucoma, and diabetic retinopathy (DR) has been explored over the past two decades. Each of the disease conditions and their corresponding animal models provide distinct challenges and unique opportunities to gain a better understanding of the role of the UPR in the maintenance of retinal health and function. Method We performed an extensive literature search on PubMed and Google Scholar using the following keywords: unfolded protein response, metabolism, ER stress, retinal degeneration, aging, age-related macular degeneration, retinitis pigmentosa, glaucoma, diabetic retinopathy. Results and conclusion We summarize recent advances in understanding cellular stress response, in particular the UPR, in retinal diseases, highlighting the potential roles of UPR pathways in regulation of cellular metabolism and mitochondrial function in retinal neurons. Further, we provide perspective on the promise and challenges for targeting the UPR pathways as a new therapeutic approach in age- and disease-related retinal degeneration.

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ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

Cited by 16 publications

References 71 publications

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

Genetic Diversity and Runs of homozygosity analysis of Hetian Sheep Populations Revealed by Illumina OvineSNP50 BeadChip

Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications

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