Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration
Szabolcs Felszeghy,
Johanna Viiri,
Jussi J. Paterno,
Juha M.T. Hyttinen,
Ali Koskela,
Mei Chen,
Henri Leinonen,
Heikki Tanila,
Niko Kivinen,
Arto Koistinen,
Elisa Toropainen,
Marialaura Amadio,
Adrian Smedowski,
Mika Reinisalo,
Mateusz Winiarczyk,
Jerzy Mackiewicz,
Maija Mutikainen,
Anna-Kaisa Ruotsalainen,
Mikko Kettunen,
Kimmo Jokivarsi,
Debasish Sinha,
Kati Kinnunen,
Goran Petrovski,
Janusz Blasiak,
Geir Bjørkøy,
Ari Koskelainen,
Heli Skottman,
Arto Urtti,
Antero Salminen,
Ram Kannan,
Deborah A. Ferrington,
Heping Xu,
Anna-Liisa Levonen,
Pasi Tavi,
Anu Kauppinen,
Kai Kaarniranta
Affiliations
Szabolcs Felszeghy
Institute of Dentistry, University of Eastern Finland, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Johanna Viiri
Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
Jussi J. Paterno
Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
Juha M.T. Hyttinen
Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
Ali Koskela
Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
Mei Chen
The Wellcome-Wolfson Institute of Experimental Medicine Queen's University Belfast, Belfast, UK
Henri Leinonen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Heikki Tanila
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Niko Kivinen
Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
Arto Koistinen
SIB Labs, University of Eastern Finland, Kuopio, Finland
Elisa Toropainen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
Marialaura Amadio
Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy
Adrian Smedowski
Chair and Department of Physiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
Mika Reinisalo
Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
Mateusz Winiarczyk
Department of Epizootiology, University of Life Sciences of Lublin, Poland; Department of Vitreoretinal Surgery, Medical University of Lublin, Poland
Jerzy Mackiewicz
Department of Vitreoretinal Surgery, Medical University of Lublin, Poland
Maija Mutikainen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Anna-Kaisa Ruotsalainen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Mikko Kettunen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Kimmo Jokivarsi
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Debasish Sinha
The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Kati Kinnunen
Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
Goran Petrovski
Centre of Eye Research, Department of Ophthalmology, Oslo University Hospital, University of Oslo, Oslo, Norway
Janusz Blasiak
Department of Molecular Genetics, University of Lodz, Lodz, Poland
Geir Bjørkøy
Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine; Norwegian University of Science and Technology and Department of Technology; University College of Sør-Trøndelag, Trondheim, Norway
Ari Koskelainen
Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Aalto, Finland
Heli Skottman
Faculty of Medicine and Life Sciences, BioMediTech Institute, University of Tampere, Tampere, Finland
Arto Urtti
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
Antero Salminen
Department of Neurology, University of Eastern Finland, Kuopio, Finland
Ram Kannan
Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, CA, USA
Deborah A. Ferrington
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, USA
Heping Xu
The Wellcome-Wolfson Institute of Experimental Medicine Queen's University Belfast, Belfast, UK
Anna-Liisa Levonen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Pasi Tavi
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Anu Kauppinen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
Kai Kaarniranta
Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland; Correspondence to: Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
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
