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.contributor.author

Cho, Kyoung-in

dc.contributor.author

Yi, Haiqing

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Tserentsoodol, Nomingerel

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Searle, Kelly

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Ferreira, Paulo A

dc.coverage.spatial

England

dc.date.accessioned

2011-06-21T17:27:33Z

dc.date.issued

2010-09

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.description.version

Version of Record

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/20682751

dc.identifier

dmm.004648

dc.identifier.eissn

1754-8411

dc.identifier.uri

https://hdl.handle.net/10161/4182

dc.language

eng

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en_US

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The Company of Biologists

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Dis Model Mech

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10.1242/dmm.004648

dc.relation.journal

Disease Models & Mechanisms

dc.subject

Animals

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COUP Transcription Factor I

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Cholesterol

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Cytoprotection

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Fatty Acids

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Haploinsufficiency

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Homeostasis

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Light

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Lipid Metabolism

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Mice

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Models, Biological

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Molecular Chaperones

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Nuclear Pore Complex Proteins

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Oxidative Stress

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Protein Binding

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Protein Isoforms

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Retinal Neurons

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Retinal Pigment Epithelium

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Signal Transduction

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Ubiquitin-Conjugating Enzymes

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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
dc.type

Journal article

duke.contributor.orcid

Ferreira, Paulo A|0000-0003-4585-1717

duke.date.pubdate

2010-10-sep

duke.description.issue

10-Sep

duke.description.volume

3

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/20682751

pubs.begin-page

595

pubs.end-page

604

pubs.issue

9-10

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

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Ophthalmology

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Pathology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

3

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