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      Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead

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          Abstract

          The retinal ganglion cells (RGCs) are the output cells of the retina into the brain. In mammals, these cells are not able to regenerate their axons after optic nerve injury, leaving the patients with optic neuropathies with permanent visual loss. An effective RGCs-directed therapy could provide a beneficial effect to prevent the progression of the disease. Axonal injury leads to the functional loss of RGCs and subsequently induces neuronal death, and axonal regeneration would be essential to restore the neuronal connectivity, and to reestablish the function of the visual system. The manipulation of several intrinsic and extrinsic factors has been proposed in order to stimulate axonal regeneration and functional repairing of axonal connections in the visual pathway. However, there is a missing point in the process since, until now, there is no therapeutic strategy directed to promote axonal regeneration of RGCs as a therapeutic approach for optic neuropathies.

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          Most cited references297

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          Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.

          The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.
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            The types of retinal ganglion cells: current status and implications for neuronal classification.

            In the retina, photoreceptors pass visual information to interneurons, which process it and pass it to retinal ganglion cells (RGCs). Axons of RGCs then travel through the optic nerve, telling the rest of the brain all it will ever know about the visual world. Research over the past several decades has made clear that most RGCs are not merely light detectors, but rather feature detectors, which send a diverse set of parallel, highly processed images of the world on to higher centers. Here, we review progress in classification of RGCs by physiological, morphological, and molecular criteria, making a particular effort to distinguish those cell types that are definitive from those for which information is partial. We focus on the mouse, in which molecular and genetic methods are most advanced. We argue that there are around 30 RGC types and that we can now account for well over half of all RGCs. We also use RGCs to examine the general problem of neuronal classification, arguing that insights and methods from the retina can guide the classification enterprise in other brain regions.
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              KLF family members regulate intrinsic axon regeneration ability.

              Neurons in the central nervous system (CNS) lose their ability to regenerate early in development, but the underlying mechanisms are unknown. By screening genes developmentally regulated in retinal ganglion cells (RGCs), we identified Krüppel-like factor-4 (KLF4) as a transcriptional repressor of axon growth in RGCs and other CNS neurons. RGCs lacking KLF4 showed increased axon growth both in vitro and after optic nerve injury in vivo. Related KLF family members suppressed or enhanced axon growth to differing extents, and several growth-suppressive KLFs were up-regulated postnatally, whereas growth-enhancing KLFs were down-regulated. Thus, coordinated activities of different KLFs regulate the regenerative capacity of CNS neurons.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                25 March 2020
                April 2020
                : 21
                : 7
                : 2262
                Affiliations
                [1 ]Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
                [2 ]Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
                [3 ]Department of Cell Biology and Histology, University of the Basque Country UPV/EHU, Leioa 48940, Vizcaya, Spain
                [4 ]Association for Innovation and Biomedical Research on Light and Image (AIBILI), 3000-548 Coimbra, Portugal
                Author notes
                [* ]Correspondence: asantiago@ 123456fmed.uc.pt ; Tel.: +351-239480226
                Author information
                https://orcid.org/0000-0002-0479-3066
                https://orcid.org/0000-0001-8384-9648
                https://orcid.org/0000-0002-0477-1641
                https://orcid.org/0000-0002-7541-7041
                Article
                ijms-21-02262
                10.3390/ijms21072262
                7177277
                32218163
                5f907379-19b1-4404-9606-50aeb4075eab
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 February 2020
                : 20 March 2020
                Categories
                Review

                Molecular biology
                retinal ganglion cells,neurodegeneration,axonal regeneration,neuroprotection,optic neuropathies

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