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Uncovering novel therapeutic targets and pathways against neurodegeneration elicited by oxidative stress
Author(s) -
Cho Kyoungin,
Yi Haiqing,
Ferreira Paulo A
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.943.5
Subject(s) - oxidative stress , neurodegeneration , microbiology and biotechnology , proteostasis , biology , retinal degeneration , chemistry , retina , neuroscience , biochemistry , medicine , disease
Oxidative stress is linked to a plethora of diseases and aging manifestations. Identification of factors modulating oxidative stress may uncover therapeutic targets to unmet clinical needs. We report that haploinsufficiency of RAN‐binding protein‐2 (RANBP2 +/− ) protects photoreceptors and the retinal pigment epithelium (RPE) from degeneration by light damage, whereas it increases and decreases the susceptibility of dopaminergic neurons of the brain and retina to MPTP toxicity, respectively. RANBP2 +/− mice upon light‐elicited oxidative stress suppresses membrane dysgenesis and modulates the levels of a subset of functionally diverse partners of RANBP2 (e.g. RAN GTPase, ubc9, S1 subunit of the 26S proteasome), ubiquitylated proteins and a set of orphan nuclear receptors. RANBP2 +/− suppresses also the oxidative stress‐induced formation of lipid deposits in the RPE. On the other hand, MPTP in RANBP2 +/− decreases the locomotor activity and leads to damage of TH + ‐neurons of SNpc, whereas it promotes an increase of GFAP + ‐glial cells and TH + ‐amacrine neurons of the retina. We found also ten brain metabolites significantly modulated by MPTP between RANBP2 +/+ and RANBP2 +/− . Hence, insufficiency of RANBP2 leads to cell‐type‐dependent regulation of proteostasis and lipid homeostasis acting on functionally interconnected pathways in response to oxidative stress. NIH support GM083165 & EY019492