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      Endoplasmic Reticulum Stress and Unfolded Protein Response Pathways: Potential for Treating Age-related Retinal Degeneration

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          Abstract

          Accumulation of misfolded proteins in the endoplasmic reticulum (ER) and their aggregation impair normal cellular function and can be toxic, leading to cell death. Prolonged expression of misfolded proteins triggers ER stress, which initiates a cascade of reactions called the unfolded protein response (UPR). Protein misfolding is the basis for a variety of disorders known as ER storage or conformational diseases. There are an increasing number of eye disorders associated with misfolded proteins and pathologic ER responses, including retinitis pigmentosa (RP). Herein we review the basic cellular and molecular biology of UPR with focus on pathways that could be potential targets for treating retinal degenerative diseases.

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          Endoplasmic reticulum stress: cell life and death decisions.

          C. Xu (2005)
          Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
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            CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.

            H Zinszner, M Kuroda, X Wang … (1998)
            Cellular stress, particularly in response to toxic and metabolic insults that perturb function of the endoplasmic reticulum (ER stress), is a powerful inducer of the transcription factor CHOP. The role of CHOP in the response of cells to injury associated with ER stress was examined in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibroblasts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function. A similar deficit in programmed cells death in response to ER stress was also observed in MEFs that lack CHOP's major dimerization partner, C/EBPbeta, implicating the CHOP-C/EBP pathway in programmed cell death. An animal model for studying the effects of chop on the response to ER stress was developed. It entailed exposing mice with defined chop genotypes to a single sublethal intraperitoneal injection of tunicamycin and resulted in a severe illness characterized by transient renal insufficiency. In chop +/+ and chop +/- mice this was associated with the early expression of CHOP in the proximal tubules followed by the development of a histological picture similar to the human condition known as acute tubular necrosis, a process that resolved by cellular regeneration. In the chop -/- animals, in spite of the severe impairment in renal function, evidence of cellular death in the kidney was reduced compared with the wild type. The proximal tubule epithelium of chop -/- animals exhibited fourfold lower levels of TUNEL-positive cells (a marker for programmed cell death), and significantly less evidence for subsequent regeneration. CHOP therefore has a role in the induction of cell death under conditions associated with malfunction of the ER and may also have a role in cellular regeneration under such circumstances.
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              Protein folding in the cell.

              M Gething, J. Sambrook (1992)
              In the cell, as in vitro, the final conformation of a protein is determined by its amino-acid sequence. But whereas some isolated proteins can be denatured and refolded in vitro in the absence of other macromolecular cellular components, folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Ophthalmic Vis Res
                Journal ID (iso-abbrev): J Ophthalmic Vis Res
                Journal ID (publisher-id): JOVR
                Title: Journal of Ophthalmic & Vision Research
                Publisher: Ophthalmic Research Center
                ISSN (Print): 2008-2010
                ISSN (Electronic): 2008-322X
                Publication date (Print): January 2012
                Volume: 7
                Issue: 1
                Pages: 45-59
                Affiliations
                SUNY Eye Institute, Departments of Neuroscience and Physiology and Ophthalmology, SUNY Upstate Medical University, Syracuse, NY, USA
                Author notes
                Correspondence to: Mohammad Haeri, MD, PhD. Departments of Neuroscience and Physiology and Ophthalmology, SUNY Upstate Medical University, WH3220, Syracuse, NY 13210, USA; Tel: +1 315 464 8148, Fax: +1 315 464 7725; e-mail: haeris@ 123456upstate.edu
                Article
                Publisher ID: jovr-07-45
                PMC ID: 3381108
                PubMed ID: 22737387
                SO-VID: 351feb67-fa9f-4d4f-ad12-4fe53f00cf78
                Copyright statement: Copyright @ 2012
                License:

                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 work is properly cited.

                History
                Date received : 14 November 2011
                Date accepted : 18 December 2011
                Categories
                Subject: Translational Eye Research

                ScienceOpen disciplines: Ophthalmology & Optometry
                Keywords: age-related retinal degeneration,unfolded protein response,retinal degenerative diseases,protein aggregation,er stress,misfolded protein
                Data availability:
                ScienceOpen disciplines: Ophthalmology & Optometry
                Keywords: age-related retinal degeneration, unfolded protein response, retinal degenerative diseases, protein aggregation, er stress, misfolded protein

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