18
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          T17M rhodopsin expression in rod photoreceptors leads to severe retinal degeneration and is associated with the activation of ER stress related Unfolded Protein Response (UPR) signaling. Here, we show a novel role of a UPR transcription factor, ATF4, in photoreceptor cellular pathology. We demonstrated a pro-death role for ATF4 overexpression during autosomal dominant retinitis pigmentosa (ADRP). Based on our results in ATF4 knockout mice and adeno-associated viral (AAV) delivery of ATF4 to the retina, we validated a novel therapeutic approach targeting ATF4 over the course of retinal degeneration. In T17M rhodopsin retinas, we observed ATF4 overexpression concomitantly with reduction of p62 and elevation of p53 levels. These molecular alterations, together with increased CHOP and caspase-3/7 activity, possibly contributed to the mechanism of photoreceptor cell loss. Conversely, ATF4 knockdown retarded retinal degeneration in 1-month-old T17M Rhodopsin mice and promoted photoreceptor survival, as measured by scotopic and photopic ERGs and photoreceptor nuclei row counts. Similarly, ATF4 knockdown also markedly delayed retinal degeneration in 3-month-old ADRP animals. This delay was accompanied by a dramatic decrease in UPR signaling, the launching of anti-oxidant defense, initiation of autophagy, and improvement of rhodopsin biosynthesis which together perhaps combat the cellular stress associated with T17M rhodopsin. Our data indicate that augmented ATF4 signals during retinal degeneration plays a cytotoxic role by triggering photoreceptor cell death. Future ADRP therapy regulating ATF4 expression can be developed to treat retinal degenerative disorders associated with activated UPR.

          Related collections

          Most cited references 44

          • Record: found
          • Abstract: found
          • Article: not found

          Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.

          Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress.

            The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response. The deleterious effects of Nrf2 or PERK deficiencies could be attenuated by the restoration of cellular glutathione levels or Nrf2 activity. In addition, the inhibition of reactive oxygen species production attenuated apoptotic induction following endoplasmic reticulum stress. Our data suggest that perturbations in cellular redox status sensitize cells to the harmful effects of endoplasmic reticulum stress, but that other factors are essential for apoptotic commitment.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.

              Induction of phase 2 enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, is an important mechanism for protection against carcinogenesis. The transcription factor Nrf2, which binds to the antioxidant response element (ARE) found in the upstream regulatory region of many phase 2 genes, is essential for the induction of these enzymes. We have investigated the effect of the potent enzyme inducer and anticarcinogen 3H-1,2-dithiole-3-thione (D3T) on the fate of Nrf2 in murine keratinocytes. Both total and nuclear Nrf2 levels increased rapidly and persistently after treatment with D3T but could be blocked by cotreatment with cycloheximide. Nrf2 mRNA levels increased approximately 2-fold 6 h after D3T treatment. To examine the transcriptional activation of Nrf2 by D3T, the proximal region (1 kb) of the nrf2 promoter was isolated. Deletion and mutagenesis analyses demonstrated that nrf2 promoter-luciferase reporter activity was enhanced by treatment with D3T and that ARE-like sequences were required for this activation. Gel shift assays with nuclear extracts from PE cells indicated that common factors bind to typical AREs and the ARE-like sequences of the nrf2 promoter. Direct binding of Nrf2 to its own promoter was demonstrated by chromatin immunoprecipitation assay. Overexpression of Nrf2 increased the activity of the nrf2 promoter-luciferase reporter, while expression of mutant Nrf2 protein repressed activity. Thus, Nrf2 appears to autoregulate its own expression through an ARE-like element located in the proximal region of its promoter, leading to persistent nuclear accumulation of Nrf2 and protracted induction of phase 2 genes in response to chemopreventive agents.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 May 2016
                2016
                : 11
                : 5
                Affiliations
                [1 ]Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [2 ]Vision Science Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [3 ]Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America
                [4 ]Center for Neurodegeneration and Experimental Therapy, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [5 ]Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [6 ]Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                Indiana University College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YB MG. Performed the experiments: YB OG SZ MG PK. Analyzed the data: YB MG MA ZB. Contributed reagents/materials/analysis tools: SZ MG. Wrote the paper: YB ZB MA MG.

                Article
                PONE-D-16-00316
                10.1371/journal.pone.0154779
                4856272
                27144303
                © 2016 Bhootada et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 8, Tables: 0, Pages: 23
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000053, National Eye Institute;
                Award ID: Grant R01EY020905
                Award Recipient :
                This work was funded by R01EY020905, P30 EY003039.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Retina
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Retina
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Afferent Neurons
                Photoreceptors
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Afferent Neurons
                Photoreceptors
                Biology and Life Sciences
                Neuroscience
                Sensory Perception
                Sensory Receptors
                Photoreceptors
                Biology and Life Sciences
                Psychology
                Sensory Perception
                Sensory Receptors
                Photoreceptors
                Social Sciences
                Psychology
                Sensory Perception
                Sensory Receptors
                Photoreceptors
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Sensory Receptors
                Photoreceptors
                Medicine and Health Sciences
                Ophthalmology
                Retinal Disorders
                Retinal Degeneration
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Autophagic Cell Death
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signaling Cascades
                Stress Signaling Cascade
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized

                Comments

                Comment on this article