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

Animals Autophagy / genetics Biomarkers Disease Models, Animal Electroretinography Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress Genetic Association Studies Genetic Predisposition to Disease Immunohistochemistry Lysosomes / metabolism Macular Degeneration / diagnosis Mice Mice, Knockout Mitochondria / metabolism Molecular Imaging Mutation NF-E2-Related Factor 2 / deficiency Oxidative Stress / genetics Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / deficiency Phenotype Photoreceptor Cells / metabolism Protein Aggregation, Pathological Reactive Oxygen Species / metabolism Retinal Pigment Epithelium / metabolism

Aging Autophagy Degeneration Oxidative stress Proteasome Protein aggregation

Journal

Redox biology

ISSN: 2213-2317

Titre abrégé: Redox Biol

Pays: Netherlands

ID NLM: 101605639

Informations de publication

Date de publication:
01 2019

Historique:

received: 13 07 2018

revised: 06 09 2018

accepted: 13 09 2018

pubmed: 27 9 2018

medline: 2 4 2019

entrez: 26 9 2018

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.redox.2018.09.011 PMID: 30253279 PMC: PMC6156745

pubmed: 30253279

pii: S2213-2317(18)30605-0

doi: 10.1016/j.redox.2018.09.011

pmc: PMC6156745

pii:

doi:

Substances chimiques

Biomarkers 0

Endoplasmic Reticulum Chaperone BiP 0

Hspa5 protein, mouse 0

NF-E2-Related Factor 2 0

Nfe2l2 protein, mouse 0

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha 0

Ppargc1a protein, mouse 0

Reactive Oxygen Species 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1-12

Informations de copyright

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