Evidence map›Paper›PMID 30253279›Full record

ArticleRedox biology2019

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 and 26 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Redox biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
112citing papers in PubMed, 2 pooled it
15.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

112 citing papers in PubMed, 2 syntheses or guidelines pooled it, 159 citations in OpenAlex.

  1. Guideline
  2. Pooled it
  3. Article
  4. Review
  5. AAV-NRF2 protects retinal and choroidal vasculature in a GDF15-dependent manner in an oxidative damage model of AMD.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  6. Article
  7. Review
  8. Functional polymorphisms in pigmentation-related genesBiochemistry and biophysics reports · 2026
    Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. Article
  14. Autophagy in ocular diseases: from mechanisms to therapeutic potential.Frontiers in cell and developmental biology · 2026
    Review
  15. Review
  16. Article
  17. Exploiting autophagy and related pathways: pioneering new horizons in cataract therapy.Apoptosis : an international journal on programmed cell death · 2025
    Review
  18. Review
  19. Article
  20. Review

52 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

36 authors at 12 institutions in 6 countries.

Szabolcs FelszeghyInstitute of Dentistry, University of Eastern Finland, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Johanna ViiriDepartment of Ophthalmology, University of Eastern Finland, Kuopio, Finland.
Jussi J PaternoDepartment of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
Juha M T HyttinenDepartment of Ophthalmology, University of Eastern Finland, Kuopio, Finland.
Ali KoskelaDepartment of Ophthalmology, University of Eastern Finland, Kuopio, Finland.
Mei ChenThe Wellcome-Wolfson Institute of Experimental Medicine Queen's University Belfast, Belfast, UK.
Henri LeinonenA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Heikki TanilaA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Niko KivinenDepartment of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
Arto KoistinenSIB Labs, University of Eastern Finland, Kuopio, Finland.
Elisa ToropainenSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Marialaura AmadioDepartment of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy.
Adrian SmedowskiChair and Department of Physiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Mika ReinisaloDepartment of Ophthalmology, University of Eastern Finland, Kuopio, Finland; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Mateusz WiniarczykDepartment of Epizootiology, University of Life Sciences of Lublin, Poland; Department of Vitreoretinal Surgery, Medical University of Lublin, Poland.
Jerzy MackiewiczDepartment of Vitreoretinal Surgery, Medical University of Lublin, Poland.
Maija MutikainenA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Anna-Kaisa RuotsalainenA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Mikko KettunenA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Kimmo JokivarsiA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Debasish SinhaThe Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Kati KinnunenDepartment of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
Goran PetrovskiCentre of Eye Research, Department of Ophthalmology, Oslo University Hospital, University of Oslo, Oslo, Norway.
Janusz BlasiakDepartment of Molecular Genetics, University of Lodz, Lodz, Poland.
Geir BjørkøyCentre 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 KoskelainenDepartment of Neuroscience and Biomedical Engineering, Aalto University School of Science, Aalto, Finland.
Heli SkottmanFaculty of Medicine and Life Sciences, BioMediTech Institute, University of Tampere, Tampere, Finland.
Arto UrttiSchool 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 SalminenDepartment of Neurology, University of Eastern Finland, Kuopio, Finland.
Ram KannanArnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, CA, USA.
Deborah A FerringtonDepartment of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, USA.
Heping XuThe Wellcome-Wolfson Institute of Experimental Medicine Queen's University Belfast, Belfast, UK.
Anna-Liisa LevonenA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Pasi TaviA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Anu KauppinenSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Kai KaarnirantaDepartment of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland. Electronic address: kai.kaarniranta@uef.fi.
University of Eastern Finland · FIMedical University of Lublin · PLQueen's University Belfast · GBUniversity of Pavia · ITDoheny Eye Institute · USJohns Hopkins University · USKuopio University Hospital · FIMedical University of Silesia · PLNorwegian University of Science and Technology · NOOslo University Hospital · NOTampere University · FIUniversity of Minnesota · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Genetic Predisposition to DiseaseAnimalsAutophagyBiomarkersDisease Models, AnimalElectroretinographyEndoplasmic Reticulum Chaperone BiPEndoplasmic Reticulum StressGenetic Association StudiesImmunohistochemistryLysosomesMacular DegenerationMiceMice, KnockoutMitochondriaMolecular ImagingBiomarkersEndoplasmic Reticulum Chaperone BiPHspa5 protein, mouseNfe2l2 protein, mouseNF-E2-Related Factor 2Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPpargc1a protein, mouseReactive Oxygen SpeciesAgingAutophagyDegenerationOxidative stressProteasomeProtein aggregation

Identifiers

PMID30253279
PMCPMC6156745
OpenAlexW2890361890

What OpenQuestion holds

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LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.