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      Loss of Daylight Vision in Retinal Degeneration: Are Oxidative Stress and Metabolic Dysregulation to Blame?*

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          Abstract

          Retinitis pigmentosa is characterized by loss of night vision, followed by complete blindness. Over 40 genetic loci for retinitis pigmentosa have been identified in humans, primarily affecting photoreceptor structure and function. The availability of excellent animal models allows for a mechanistic characterization of the disease. Metabolic dysregulation and oxidative stress have been found to correlate with the loss of vision, particularly in cones, the type of photoreceptors that mediate daylight and color vision. The evidence that these problems actually cause loss of vision and potential therapeutic approaches targeting them are discussed.

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          Most cited references78

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          Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.

          Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
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            Oxidant signals and oxidative stress.

            Although oxidants clearly possess the capacity to behave in a random and destructive fashion, growing evidence suggests that in many instances the production of reactive oxygen species is tightly regulated and their downstream targets exquisitely specific. This past year, several notable advances have been made in defining the specific redox-dependent targets of intracellular oxidants, as well as the myriad pathways that appear to employ oxidants as effector molecules. These new studies have significantly altered our understanding of how reactive oxygen species participate in diverse processes from tumourigenesis to ageing.
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              Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration.

              The death of photoreceptor cells caused by retinal degenerative diseases often results in a complete loss of retinal responses to light. We explore the feasibility of converting inner retinal neurons to photosensitive cells as a possible strategy for imparting light sensitivity to retinas lacking rods and cones. Using delivery by an adeno-associated viral vector, here, we show that long-term expression of a microbial-type rhodopsin, channelrhodopsin-2 (ChR2), can be achieved in rodent inner retinal neurons in vivo. Furthermore, we demonstrate that expression of ChR2 in surviving inner retinal neurons of a mouse with photoreceptor degeneration can restore the ability of the retina to encode light signals and transmit the light signals to the visual cortex. Thus, expression of microbial-type channelrhodopsins, such as ChR2, in surviving inner retinal neurons is a potential strategy for the restoration of vision after rod and cone degeneration.
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                Author and article information

                Journal
                J Biol Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                0021-9258
                1083-351X
                13 January 2012
                10 November 2011
                10 November 2011
                : 287
                : 3
                : 1642-1648
                Affiliations
                From the []Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01606 and
                the [§ ]Departments of Genetics and Ophthalmology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115
                Author notes
                [2 ] To whom correspondence should be addressed. E-mail: cepko@ 123456genetics.med.harvard.edu .
                [1]

                Postdoctoral Fellow of the Howard Hughes Medical Institute.

                Article
                R111.304428
                10.1074/jbc.R111.304428
                3265845
                22074929
                72e3d5bb-6a5c-4516-a375-37eb8c36acb0
                © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version full access.

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                Biochemistry
                retinal degeneration,metabolism,oxidative stress,photoreceptors,gene therapy
                Biochemistry
                retinal degeneration, metabolism, oxidative stress, photoreceptors, gene therapy

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