9
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells

      research-article

      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

          The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs.

          Related collections

          Most cited references23

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

          Induced pluripotent stem cells: past, present, and future.

          The development of iPSCs reflected the merging of three major scientific streams and has in turn led to additional new branches of investigation. However, there is still debate about whether iPSCs are functionally equivalent to ESCs. This question should be answered only by science, not by politics or business. Copyright © 2012 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            AMPA receptor trafficking at excitatory synapses.

            Excitatory synapses in the CNS release glutamate, which acts primarily on two sides of ionotropic receptors: AMPA receptors and NMDA receptors. AMPA receptors mediate the postsynaptic depolarization that initiates neuronal firing, whereas NMDA receptors initiate synaptic plasticity. Recent studies have emphasized that distinct mechanisms control synaptic expression of these two receptor classes. Whereas NMDA receptor proteins are relatively fixed, AMPA receptors cycle synaptic membranes on and off. A large family of interacting proteins regulates AMPA receptor turnover at synapses and thereby influences synaptic strength. Furthermore, neuronal activity controls synaptic AMPA receptor trafficking, and this dynamic process plays a key role in the synaptic plasticity that is thought to underlie aspects of learning and memory.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Mouse mtDNA mutant model of Leber hereditary optic neuropathy.

              An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress.
                Bookmark

                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                21 June 2019
                June 2019
                : 8
                : 6
                : 625
                Affiliations
                [1 ]Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan; molly0103@ 123456gmail.com (Y.-P.Y.); yarmishyn@ 123456gmail.com (A.A.Y.); backyard0826@ 123456gmail.com (T.-W.L.); cschien6688@ 123456gmail.com (C.-S.C.); shchiou@ 123456vghtpe.gov.tw (S.-H.C.)
                [2 ]School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; taichilin@ 123456hotmail.com (T.-C.L.); m95gbk@ 123456gmail.com (D.-K.H.); dac58@ 123456tpech.gov.tw (C.-Y.T.); sjchen@ 123456vghtpe.gov.tw (S.-J.C.)
                [3 ]School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan
                [4 ]Cancer Center, Taipei Veterans General Hospital, Taipei 112, Taiwan; nguyennhi204@ 123456hotmail.com
                [5 ]Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan
                [6 ]Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
                [7 ]Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, Taiwan
                [8 ]Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan; poohlilidada@ 123456gmail.com
                [9 ]Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan; chiougy@ 123456hotmail.com
                [10 ]Department of Ophthalmology, Taipei City Hospital, Taipei 103, Taiwan
                [11 ]Genomic Research Center, Academia Sinica, Taipei 115, Taiwan
                [12 ]Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
                [13 ]Department of Ophthalmology, Fu-Jen Catholic University, Taipei 242, Taiwan
                Author notes
                [* ]Correspondence: chpeng1008@ 123456gmail.com (C.-H.P.); chihchienym@ 123456gmail.com (C.-C.H.); Tel.: +886-2-28332211 (C.-H.P.); +886-2-28757394 (C.-C.H.)
                Author information
                https://orcid.org/0000-0001-9666-1273
                https://orcid.org/0000-0003-2354-2999
                Article
                cells-08-00625
                10.3390/cells8060625
                6627514
                31234430
                c03b5894-b7b0-4745-945e-0dd0fbdc1397
                © 2019 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
                : 21 May 2019
                : 19 June 2019
                Categories
                Article

                leber’s hereditary optic neuropathy (lhon),retina,retinal ganglion cell,glutamate,ampa receptor

                Comments

                Comment on this article