Purchase this article with an account.
Kyoung-in Cho, Haiqing Yi, Paulo A. Ferreira; Uncovering Novel Therapeutic Targets Promoting Neuroprotection Against Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1387.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Oxidative stress is linked to a plethora of diseases and aging manifestations affecting retinal neurons. Identification of factors modulating oxidative stress may uncover therapeutic targets to unmet clinical needs. Oxidative stress elicited by bright light and the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a deleterious risk factor linked to neurodegenerative diseases, such as age-related macular degeneration and Parkinson’s disease. The former leads to the degeneration of photoreceptors, while the latter causes the loss of dopaminergic neurons (DA) of the substantia nigra (SNpc). This study aims at defining the role of insufficiency of RAN-binding protein-2 (RANBP2) and its partners in promoting neuroprotection in response to chronic and bright light, and exposure to MPTP.
We employed wild-type and inbred haploinsufficient RANBP2 mice exposed to cyclic\low or chronic\bright light conditions or acute MPTP administration. Immunohistochemistry of the retina and brain for a variety of proteins, such as partners of RANBP2 and markers for cell death, glyosis and DA neurons, was used to assess changes in cell populations and their molecular state. A metabolomic approach was also used to identify signature markers between wild-type and RANBP2+/- mice exposed to MPTP.
Haploinsufficiency of RANBP2 protects the retinal pigment epithelium (RPE), and photoreceptors from degeneration, by light damage, whereas it increases and decreases the susceptibility of DA neurons of the brain and retina to MPTP toxicity, respectively. RANBP2+/- upon bright light-elicited oxidative stress suppresses membrane dysgenesis and modulates the levels of a subset of functionally diverse partners of RANBP2, 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+/- mice decreases the locomotor activity (open field test) and leads to transient damage of TH+-neurons of the 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 wild-type and RANBP2+/- mice.
Haploinsufficiency of RANBP2 promotes cell-type-dependent neuroprotection or neurogenesis, regulation of lipid homeostasis and proteostasis of a subset of acessory proteins of RANBP2 that act on functionally interconnected pathways in response to oxidative stress. Such proteins emerge as therapeutic targets to promote neuroprotection.
This PDF is available to Subscribers Only