Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration
| Autor: | Anna-Kaisa Ruotsalainen, Mikko I. Kettunen, Heping Xu, Maija Mutikainen, Goran Petrovski, Ali Koskela, Adrian Smedowski, Mika Reinisalo, Mateusz Winiarczyk, Heikki Tanila, Kai Kaarniranta, Juha M.T. Hyttinen, Szabolcs Felszeghy, Janusz Blasiak, Kati Kinnunen, Anna-Liisa Levonen, Pasi Tavi, Ari Koskelainen, Jussi J. Paterno, Debasish Sinha, Arto Urtti, Arto Koistinen, Jerzy Mackiewicz, Johanna Viiri, Heli Skottman, Elisa Toropainen, Marialaura Amadio, Ram Kannan, Niko Kivinen, Geir Bjørkøy, Deborah A. Ferrington, Henri Leinonen, Mei Chen, Kimmo Jokivarsi, Anu Kauppinen, Antero Salminen |
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| Přispěvatelé: | Division of Pharmaceutical Biosciences, Drug Research Program, Drug Delivery Unit, University of Eastern Finland, Queen's University Belfast, University of Pavia, Medical University of Silesia in Katowice, University of Life Sciences in Lublin, Medical University of Lublin, Johns Hopkins University, University of Oslo, University of Łódź, Norwegian University of Science and Technology, Department of Neuroscience and Biomedical Engineering, Tampere University, University of Southern California, University of Minnesota Twin Cities, Aalto-yliopisto, Aalto University |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Aging Clinical Biochemistry Cellular detoxification TRANSCRIPTION FACTOR NRF2 Retinal Pigment Epithelium Biochemistry Macular Degeneration Mice 0302 clinical medicine ANTIOXIDANT RESPONSE lcsh:QH301-705.5 Endoplasmic Reticulum Chaperone BiP ta116 Mice Knockout lcsh:R5-920 education.field_of_study Chemistry Endoplasmic Reticulum Stress Immunohistochemistry Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mitochondria Molecular Imaging 3. Good health Cell biology Phenotype medicine.anatomical_structure RPE Protein aggregation lcsh:Medicine (General) NF-E2-Related Factor 2 Protein degradation Protein Aggregation Pathological 03 medical and health sciences Sequestosome 1 INFLAMMATION Electroretinography Autophagy medicine Animals Genetic Predisposition to Disease Photoreceptor Cells education Genetic Association Studies DYSREGULATION Retinal pigment epithelium Proteasome Endoplasmic reticulum Organic Chemistry ATF4 DEGRADATION eye diseases Protein ubiquitination Disease Models Animal 030104 developmental biology lcsh:Biology (General) Oxidative stress CELLS Mutation Degeneration 1182 Biochemistry cell and molecular biology sense organs Lysosomes Reactive Oxygen Species Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | Felszeghy, S, Viiri, J, Paterno, J J, Hyttinen, J M T, Koskela, A, Chen, M, Leinonen, H, Tanila, H, Kivinen, N, Koistinen, A, Toropainen, E, Amadio, M, Smedowski, A, Reinisalo, M, Winiarczyk, M, Mackiewicz, J, Mutikainen, M, Ruotsalainen, A K, Kettunen, M, Jokivarsi, K, Sinha, D, Kinnunen, K, Petrovski, G, Blasiak, J, Bjørkøy, G, Koskelainen, A, Skottman, H, Urtti, A, Salminen, A, Kannan, R, Ferrington, D A, Xu, H, Levonen, A L, Tavi, P, Kauppinen, A & Kaarniranta, K 2019, ' Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration ', Redox Biology, vol. 20, pp. 1-12 . https://doi.org/10.1016/j.redox.2018.09.011 Felszeghy, Viiri, Paterno, Hyttinen, Koskela,, Chen, M, Leinonen, Tanila, Kivinen, Koistinen, Totopainen, Amadio, Smedowski, Reinisalo, Winiarczyk, Mackiewicz, Mutikainen,, Xu, H & Kaarniranta 2019, ' Loss of NRF-2 and PGC-1a genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration ' Redox Biology, vol. 20, pp. 1-12 . https://doi.org/10.1016/j.redox.2018.09.011 Redox Biology Redox Biology, Vol 20, Iss, Pp 1-12 (2019) |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2018.09.011 |
| Popis: | Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells. NRF-2 (nuclear factor-erythroid 2-related factor-2) and PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC-1α in the regulation of RPE cell structure and function by using global double knockout (dKO) mice. The NRF-2/PGC-1α dKO mice exhibited significant age-dependent RPE degeneration, accumulation of the oxidative stress marker, 4-HNE (4-hydroxynonenal), the endoplasmic reticulum stress markers GRP78 (glucose-regulated protein 78) and ATF4 (activating transcription factor 4), and damaged mitochondria. Moreover, levels of protein ubiquitination and autophagy markers p62/SQSTM1 (sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta) were significantly increased together with the Iba-1 (ionized calcium binding adaptor molecule 1) mononuclear phagocyte marker and an enlargement of RPE size. These histopathological changes of RPE were accompanied by photoreceptor dysmorphology and vision loss as revealed by electroretinography. Consequently, these novel findings suggest that the NRF-2/PGC-1α dKO mouse is a valuable model for investigating the role of proteasomal and autophagy clearance in the RPE and in the development of dry AMD. Keywords: Aging, Autophagy, Degeneration, Oxidative stress, Protein aggregation, Proteasome |
| Databáze: | OpenAIRE |
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