title: The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells.
abstract: Accumulation and aggregation of misfolded proteins is a hallmark of several diseases collectively known as proteinopathies. Autophagy has a cytoprotective role in diseases associated with protein aggregates. Age-related macular degeneration (AMD) is the most common neurodegenerative eye disease that evokes blindness in elderly. AMD is characterized by degeneration of retinal pigment epithelial (RPE) cells and leads to loss of photoreceptor cells and central vision. The initial phase associates with accumulation of intracellular lipofuscin and extracellular deposits called drusen. Epidemiological studies have suggested an inverse correlation between dietary intake of marine n-3 polyunsaturated fatty acids (PUFAs) and the risk of developing neurodegenerative diseases, including AMD. However, the disease-preventive mechanism(s) mobilized by n-3 PUFAs is not completely understood. In human retinal pigment epithelial cells we find that physiologically relevant doses of the n-3 PUFA docosahexaenoic acid (DHA) induce a transient increase in cellular reactive oxygen species (ROS) levels that activates the oxidative stress response regulator NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2). Simultaneously, there is a transient increase in intracellular protein aggregates containing SQSTM1/p62 (sequestosome 1) and an increase in autophagy. Pretreatment with DHA rescues the cells from cell cycle arrest induced by misfolded proteins or oxidative stress. Cells with a downregulated oxidative stress response, or autophagy, respond with reduced cell growth and survival after DHA supplementation. These results suggest that DHA both induces endogenous antioxidants and mobilizes selective autophagy of misfolded proteins. Both mechanisms could be relevant to reduce the risk of developing aggregate-associate diseases such as AMD.
authors.affiliation: a Department of Laboratory Medicine ; Children's and Women's Health; Faculty of Medicine; Norwegian University of Science and Technology ; Trondheim , Norway.|b Department of Technology ; University College of Sør-Trøndelag ; Trondheim , Norway.|c Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine ; Norwegian University of Science and Technology ; Trondheim , Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Johansson
authors.affiliation: a Department of Laboratory Medicine ; Children's and Women's Health; Faculty of Medicine; Norwegian University of Science and Technology ; Trondheim , Norway.
authors.forename: Vivi Talstad
authors.initials: VT
authors.lastname: Monsen
authors.affiliation: a Department of Laboratory Medicine ; Children's and Women's Health; Faculty of Medicine; Norwegian University of Science and Technology ; Trondheim , Norway.|b Department of Technology ; University College of Sør-Trøndelag ; Trondheim , Norway.|c Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine ; Norwegian University of Science and Technology ; Trondheim , Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Pettersen
authors.affiliation: b Department of Technology ; University College of Sør-Trøndelag ; Trondheim , Norway.|c Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine ; Norwegian University of Science and Technology ; Trondheim , Norway.|d Department of Cancer Research and Molecular Medicine ; Faculty of Medicine; Norwegian University of Science and Technology ; Trondheim , Norway.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mildenberger
authors.affiliation: d Department of Cancer Research and Molecular Medicine ; Faculty of Medicine; Norwegian University of Science and Technology ; Trondheim , Norway.|e KG Jebsen Center for Myeloma Research; Norwegian University of Science and Technology ; Trondheim , Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Misund
authors.affiliation: f Department of Ophthalmology ; Institute of Clinical Medicine; University of Eastern Finland ; Kuopio , Finland.|g Department of Ophthalmology ; Kuopio University Hospital ; Kuopio , Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.affiliation: a Department of Laboratory Medicine ; Children's and Women's Health; Faculty of Medicine; Norwegian University of Science and Technology ; Trondheim , Norway.
authors.forename: Svanhild
authors.initials: S
authors.lastname: Schønberg
authors.affiliation: b Department of Technology ; University College of Sør-Trøndelag ; Trondheim , Norway.|c Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine ; Norwegian University of Science and Technology ; Trondheim , Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Bjørkøy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D059001:Aquatic Organisms / Q000737:chemistry; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D066329:Protein Aggregates / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D004281:Docosahexaenoic Acids
keywords: AA; DHA; HMOX1; LC3B; MAP1LC3B; NFE2L2; NRF2; OA; PUFA; ROS; SQSTM1; antioxidants; autophagy; omega-3; p62