Article: Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection

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TitleBlocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection
AuthorsFu, QL2
Hu, B2
Wu, T2
Pepinsky, RB
Mi, S3
So, KF1 2
Issue Date2008
PublisherAssociation for Research in Vision and Ophthalmology. The Journal's web site is located at http://www.iovs.org
CitationInvestigative Ophthalmology And Visual Science, 2008, v. 49 n. 3, p. 975-985 [How to Cite?]
DOI: http://dx.doi.org/10.1167/iovs.07-1199
AbstractPURPOSE. 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 antiLINGO-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. Copyright © Association for Research in Vision and Ophthalmology.
ISSN0146-0404
2011 Impact Factor: 3.597
2011 SCImago Journal Rankings: 0.320
DOIhttp://dx.doi.org/10.1167/iovs.07-1199
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorFu, QL
dc.contributor.authorHu, B
dc.contributor.authorWu, T
dc.contributor.authorPepinsky, RB
dc.contributor.authorMi, S
dc.contributor.authorSo, KF
dc.date.accessioned2010-09-06T05:54:25Z
dc.date.available2010-09-06T05:54:25Z
dc.date.issued2008
dc.description.abstractPURPOSE. 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 antiLINGO-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. Copyright © Association for Research in Vision and Ophthalmology.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationInvestigative Ophthalmology And Visual Science, 2008, v. 49 n. 3, p. 975-985 [How to Cite?]
DOI: http://dx.doi.org/10.1167/iovs.07-1199
dc.identifier.doihttp://dx.doi.org/10.1167/iovs.07-1199
dc.identifier.epage985
dc.identifier.hkuros151698
dc.identifier.isiWOS:000253812900023
dc.identifier.issn0146-0404
2011 Impact Factor: 3.597
2011 SCImago Journal Rankings: 0.320
dc.identifier.issue3
dc.identifier.openurl
dc.identifier.scopuseid_2-s2.0-41949111140
dc.identifier.spage975
dc.identifier.urihttp://hdl.handle.net/10722/67358
dc.identifier.volume49
dc.languageeng
dc.publisherAssociation for Research in Vision and Ophthalmology. The Journal's web site is located at http://www.iovs.org
dc.publisher.placeUnited States
dc.relation.ispartofInvestigative Ophthalmology and Visual Science
dc.relation.referencesReferences in Scopus
dc.titleBlocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. The University of Hong Kong
  3. Biogen IDEC