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

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dc.contributor Aalto-yliopisto fi
dc.contributor Aalto University en
dc.contributor.author Felszeghy, Szabolcs
dc.contributor.author Viiri, Johanna
dc.contributor.author Paterno, Jussi J.
dc.contributor.author Hyttinen, Juha M.T.
dc.contributor.author Koskela, Ali
dc.contributor.author Chen, Mei
dc.contributor.author Leinonen, Henri
dc.contributor.author Tanila, Heikki
dc.contributor.author Kivinen, Niko
dc.contributor.author Koistinen, Arto
dc.contributor.author Toropainen, Elisa
dc.contributor.author Amadio, Marialaura
dc.contributor.author Smedowski, Adrian
dc.contributor.author Reinisalo, Mika
dc.contributor.author Winiarczyk, Mateusz
dc.contributor.author Mackiewicz, Jerzy
dc.contributor.author Mutikainen, Maija
dc.contributor.author Ruotsalainen, Anna Kaisa
dc.contributor.author Kettunen, Mikko
dc.contributor.author Jokivarsi, Kimmo
dc.contributor.author Sinha, Debasish
dc.contributor.author Kinnunen, Kati
dc.contributor.author Petrovski, Goran
dc.contributor.author Blasiak, Janusz
dc.contributor.author Bjørkøy, Geir
dc.contributor.author Koskelainen, Ari
dc.contributor.author Skottman, Heli
dc.contributor.author Urtti, Arto
dc.contributor.author Salminen, Antero
dc.contributor.author Kannan, Ram
dc.contributor.author Ferrington, Deborah A.
dc.contributor.author Xu, Heping
dc.contributor.author Levonen, Anna Liisa
dc.contributor.author Tavi, Pasi
dc.contributor.author Kauppinen, Anu
dc.contributor.author Kaarniranta, Kai
dc.date.accessioned 2018-10-16T08:56:47Z
dc.date.available 2018-10-16T08:56:47Z
dc.date.issued 2019-01-01
dc.identifier.citation 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 . DOI: 10.1016/j.redox.2018.09.011 en
dc.identifier.issn 2213-2317
dc.identifier.other PURE UUID: d666ee06-e6b6-45a1-9589-d25cf66d9088
dc.identifier.other PURE ITEMURL: https://research.aalto.fi/en/publications/loss-of-nrf2-and-pgc1-genes-leads-to-retinal-pigment-epithelium-damage-resembling-dry-agerelated-macular-degeneration(d666ee06-e6b6-45a1-9589-d25cf66d9088).html
dc.identifier.other PURE LINK: http://www.scopus.com/inward/record.url?scp=85053754150&partnerID=8YFLogxK
dc.identifier.other PURE FILEURL: https://research.aalto.fi/files/28518376/1_s2.0_S2213231718306050_main.pdf
dc.identifier.uri https://aaltodoc.aalto.fi/handle/123456789/34323
dc.description.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. en
dc.format.extent 12
dc.format.extent 1-12
dc.format.mimetype application/pdf
dc.language.iso en en
dc.relation.ispartofseries Redox Biology en
dc.relation.ispartofseries Volume 20 en
dc.rights openAccess en
dc.subject.other Organic Chemistry en
dc.subject.other Clinical Biochemistry en
dc.subject.other 116 Chemical sciences en
dc.title Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration en
dc.type A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä fi
dc.description.version Peer reviewed en
dc.contributor.department University of Eastern Finland
dc.contributor.department Queen's University Belfast
dc.contributor.department University of Pavia
dc.contributor.department Medical University of Silesia in Katowice
dc.contributor.department University of Life Sciences in Lublin
dc.contributor.department Medical University of Lublin
dc.contributor.department Johns Hopkins University
dc.contributor.department University of Oslo
dc.contributor.department University of Lódz
dc.contributor.department Norwegian University of Science and Technology
dc.contributor.department Department of Neuroscience and Biomedical Engineering
dc.contributor.department Tampere University
dc.contributor.department University of Southern California
dc.contributor.department University of Minnesota
dc.subject.keyword Aging
dc.subject.keyword Autophagy
dc.subject.keyword Degeneration
dc.subject.keyword Oxidative stress
dc.subject.keyword Proteasome
dc.subject.keyword Protein aggregation
dc.subject.keyword Organic Chemistry
dc.subject.keyword Clinical Biochemistry
dc.subject.keyword 116 Chemical sciences
dc.identifier.urn URN:NBN:fi:aalto-201810165400
dc.identifier.doi 10.1016/j.redox.2018.09.011
dc.type.version publishedVersion


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