Chapter 17 - Neuroprotection of Retinal Ganglion Cells in Glaucoma by Blocking LINGO-1 Function or Using a Nogo-66 Receptor Antagonist

Abstract

Glaucoma is a progressive neuropathy characterized by loss of vision as a result of the death of retinal ganglion cells (RGCs). There are currently no effective neuroprotectants to treat this disorder. In this series of studies, we used LINGO-1 antagonists, Nogo-66 receptor (NgR1) antagonists, sNgR-Fc, and brain-derived neurotrophic factor (BDNF) to study the neuroprotection of RGCs in a rat glaucoma model with chronic ocular hypertension. LINGO-1 is a functional member of the NgR1/TROY and the P75 signaling complexes that prevent axonal regeneration by activating RhoA in the central nervous system (CNS). NgR1 mediates the inhibition of axonal regeneration in the presence of three myelin proteins including Nogo-A, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein in the CNS. LINGO-1 was expressed in RGCs and increased after the induction of ocular hypertension. Blocking LINGO-1 function with LINGO-1 soluble protein, LINGO-1-Fc, and LINGO-1 mAb 1A7 significantly promoted RGC survival 2 and 4weeks after the induction of ocular hypertension and also after optic nerve transection. LINGO-1 formed a receptor complex with TrkB and negatively regulated its activation in the retina after ocular hypertension injury. Blocking LINGO-1 function with LINGO-1-Fc or 1A7 upregulated TrkB phosphorylation after high intraocular pressure injury. BDNF antibody significantly blocked the neuroprotection of LINGO-1-Fc on RGC survival. Similarly, in combination with BDNF, LINGO-1-Fc provided significantly more protection to RGCs in the 4-week glaucoma animals. Thus, LINGO-1 antagonists protect RGCs by regulating the BDNF and TrkB signaling in glaucoma. NgR1 was expressed in RGCs and increased after the induction of ocular hypertension. There was synaptic degeneration of RGCs already detected in the early stage under the elevated intraocular pressure, which preceded cell death in the early stage. The upregulation of Nogo-A may be a possible mechanism of RGC death and synapse degeneration in glaucoma. Soluble (s) NgR-Fc significantly promoted RGC survival at 2 and 4weeks after ocular hypertension and also after optic nerve transection. Furthermore, sNgR-Fc relieved synaptic degeneration at 5days, and at 2 and 4weeks. This suggests that there indeed may be an opportunity to rescue RGCs that are undergoing synaptic alteration, but not yet committed to die. These data suggest that the antagonists of LINGO-1 and NgR1 may provide an attractive therapeutic strategy to prevent the degeneration of RGCs and synapses in glaucoma.