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Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection.
Invest Ophthalmol Vis Sci. 2008 Mar; 49(3):975-85.IO

Abstract

PURPOSE

LINGO-1 is a functional member of the Nogo66 receptor (NgR1)/p75 and NgR1/TROY signaling complexes that prevent axonal regeneration through RhoA in the central nervous system. LINGO-1 also promotes cell death after neuronal injury and spinal cord injury. The authors sought to examine whether blocking LINGO-1 function with LINGO-1 antagonists promotes retinal ganglion cell (RGC) survival after ocular hypertension and optic nerve transection.

METHODS

An experimental ocular hypertension model was induced in adult rats using an argon laser to photocoagulate the episcleral and limbal veins. LINGO-1 expression in the retinas was investigated using immunohistochemistry and Western blotting. Soluble LINGO-1 protein (LINGO-1-Fc) and anti-LINGO-1 mAb 1A7 were injected into the vitreous body to examine their effects on RGC survival after ocular hypertension and optic nerve transection. Signal transduction pathways mediating neuroprotective LINGO-1-Fc effects were characterized using Western blotting and specific kinase inhibitors.

RESULTS

LINGO-1 was expressed in RGCs and up-regulated after intraocular pressure elevation. Blocking LINGO-1 function with LINGO-1 antagonists, LINGO-1-Fc and 1A7 significantly reduced RGC loss 2 and 4 weeks after ocular hypertension and also promoted RGC survival after optic nerve transection. LINGO-1-Fc treatment blocked the RhoA, JNK pathway and promoted Akt activation. LINGO-1-Fc induced Akt phosphorylation, and the survival effect of LINGO-1 antagonists was abolished by Akt phosphorylation inhibitor.

CONCLUSIONS

The authors demonstrated that blocking LINGO-1 function with LINGO-1 antagonists rescues RGCs from cell death after ocular hypertension and optic nerve transection. They also delineated the RhoA and PI-3K/Akt pathways as the predominant mediator of LINGO-1-Fc neuroprotection in this paradigm of RGC death.

Authors+Show Affiliations

Department of Anatomy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18326721

Citation

Fu, Qing-Ling, et al. "Blocking LINGO-1 Function Promotes Retinal Ganglion Cell Survival Following Ocular Hypertension and Optic Nerve Transection." Investigative Ophthalmology & Visual Science, vol. 49, no. 3, 2008, pp. 975-85.
Fu QL, Hu B, Wu W, et al. Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection. Invest Ophthalmol Vis Sci. 2008;49(3):975-85.
Fu, Q. L., Hu, B., Wu, W., Pepinsky, R. B., Mi, S., & So, K. F. (2008). Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection. Investigative Ophthalmology & Visual Science, 49(3), 975-85. https://doi.org/10.1167/iovs.07-1199
Fu QL, et al. Blocking LINGO-1 Function Promotes Retinal Ganglion Cell Survival Following Ocular Hypertension and Optic Nerve Transection. Invest Ophthalmol Vis Sci. 2008;49(3):975-85. PubMed PMID: 18326721.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection. AU - Fu,Qing-Ling, AU - Hu,Bing, AU - Wu,Wutian, AU - Pepinsky,R Blake, AU - Mi,Sha, AU - So,Kwok-Fai, PY - 2008/3/11/pubmed PY - 2008/4/16/medline PY - 2008/3/11/entrez SP - 975 EP - 85 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 49 IS - 3 N2 - PURPOSE: LINGO-1 is a functional member of the Nogo66 receptor (NgR1)/p75 and NgR1/TROY signaling complexes that prevent axonal regeneration through RhoA in the central nervous system. LINGO-1 also promotes cell death after neuronal injury and spinal cord injury. The authors sought to examine whether blocking LINGO-1 function with LINGO-1 antagonists promotes retinal ganglion cell (RGC) survival after ocular hypertension and optic nerve transection. METHODS: An experimental ocular hypertension model was induced in adult rats using an argon laser to photocoagulate the episcleral and limbal veins. LINGO-1 expression in the retinas was investigated using immunohistochemistry and Western blotting. Soluble LINGO-1 protein (LINGO-1-Fc) and anti-LINGO-1 mAb 1A7 were injected into the vitreous body to examine their effects on RGC survival after ocular hypertension and optic nerve transection. Signal transduction pathways mediating neuroprotective LINGO-1-Fc effects were characterized using Western blotting and specific kinase inhibitors. RESULTS: LINGO-1 was expressed in RGCs and up-regulated after intraocular pressure elevation. Blocking LINGO-1 function with LINGO-1 antagonists, LINGO-1-Fc and 1A7 significantly reduced RGC loss 2 and 4 weeks after ocular hypertension and also promoted RGC survival after optic nerve transection. LINGO-1-Fc treatment blocked the RhoA, JNK pathway and promoted Akt activation. LINGO-1-Fc induced Akt phosphorylation, and the survival effect of LINGO-1 antagonists was abolished by Akt phosphorylation inhibitor. CONCLUSIONS: The authors demonstrated that blocking LINGO-1 function with LINGO-1 antagonists rescues RGCs from cell death after ocular hypertension and optic nerve transection. They also delineated the RhoA and PI-3K/Akt pathways as the predominant mediator of LINGO-1-Fc neuroprotection in this paradigm of RGC death. SN - 0146-0404 UR - https://www.unboundmedicine.com/medline/citation/18326721/Blocking_LINGO_1_function_promotes_retinal_ganglion_cell_survival_following_ocular_hypertension_and_optic_nerve_transection_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.07-1199 DB - PRIME DP - Unbound Medicine ER -