Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection.
OBJECTIVE
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.
Fu
Qing-Ling
QL
Department of Anatomy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
Hu
Bing
B
Wu
Wutian
W
Pepinsky
R Blake
RB
Mi
Sha
S
So
Kwok-Fai
KF
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D007429:Intraocular Pressure; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009798:Ocular Hypertension / Q000378:metabolism*; D020221:Optic Nerve Injuries / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation; D014822:Vitreous Body; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019138:Antibodies, Blocking; C525164:LINGO1 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein