Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration

Szabolcs Felszeghy(University of Eastern Finland), Johanna Viiri(University of Eastern Finland), Jussi J. Paterno(University of Eastern Finland), Juha M. T. Hyttinen(University of Eastern Finland), Ali Koskela(University of Eastern Finland), Mei Chen(Queen's University Belfast), Henri Leinonen(University of Eastern Finland), Heikki Tanila(University of Eastern Finland), Niko Kivinen(University of Eastern Finland), Arto Koistinen(University of Eastern Finland), Elisa Toropainen(University of Eastern Finland), Marialaura Amadio(University of Pavia), Adrian Smędowski(Medical University of Silesia), Mika Reinisalo(University of Eastern Finland), Mateusz Winiarczyk(Medical University of Lublin), Jerzy Mackiewicz(Medical University of Lublin), Maija Mutikainen(University of Eastern Finland), Anna‐Kaisa Ruotsalainen(University of Eastern Finland), Mikko I. Kettunen(University of Eastern Finland), Kimmo Jokivarsi(University of Eastern Finland), Debasish Sinha(Johns Hopkins University), Kati Kinnunen(Kuopio University Hospital), Goran Petrovski(Oslo University Hospital), Janusz Błasiak(University of Eastern Finland), Geir Bjørkøy(Norwegian University of Science and Technology), Ari Koskelainen(University of Pavia), Heli Skottman(Tampere University), Arto Urtti(University of Eastern Finland), Antero Salminen(University of Eastern Finland), Ram Kannan(Doheny Eye Institute), Deborah A. Ferrington(University of Minnesota), Heping Xu(Queen's University Belfast), Anna–Liisa Levonen(University of Eastern Finland), Pasi Tavi(University of Eastern Finland), Anu Kauppinen(University of Eastern Finland), Kai Kaarniranta(University of Eastern Finland)
Redox Biology
September 14, 2018
10.1016/j.redox.2018.09.011
Cited by 160Open Access
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Abstract

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.

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