Show simple item record Cho, KI Yi, H Tserentsoodol, N Searle, K Ferreira, PA
dc.coverage.spatial England 2011-06-21T17:27:33Z 2010-09
dc.identifier dmm.004648
dc.identifier.citation Dis Model Mech, 2010, 3 (9-10), pp. 595 - 604
dc.description.abstract Oxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.
dc.format.extent 595 - 604
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof Dis Model Mech
dc.relation.isversionof 10.1242/dmm.004648
dc.subject Animals
dc.subject COUP Transcription Factor I
dc.subject Cholesterol
dc.subject Cytoprotection
dc.subject Fatty Acids
dc.subject Haploinsufficiency
dc.subject Homeostasis
dc.subject Light
dc.subject Lipid Metabolism
dc.subject Mice
dc.subject Models, Biological
dc.subject Molecular Chaperones
dc.subject Nuclear Pore Complex Proteins
dc.subject Oxidative Stress
dc.subject Protein Binding
dc.subject Protein Isoforms
dc.subject Retinal Neurons
dc.subject Retinal Pigment Epithelium
dc.subject Signal Transduction
dc.subject Ubiquitin-Conjugating Enzymes
dc.subject Ubiquitinated Proteins
dc.title Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-10-sep en_US
duke.description.endpage 604 en_US
duke.description.issue 10-Sep en_US
duke.description.startpage 595 en_US
duke.description.volume 3 en_US
dc.relation.journal Disease Models & Mechanisms en_US
pubs.issue 9-10
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Ophthalmology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.publication-status Published
pubs.volume 3
dc.identifier.eissn 1754-8411

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