Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism

Pauline Dergham,Shi ZhiHua,Kenneth E. Neet,Jing Xu,Sang B. Woo,H. Uri Saragovi,Hrishikesh M. Mehta,Alba Galan,Jose Carlos Rivera,Hinyu Nedev,Marinko V. Sarunic,Yujing Bai

doi:10.1074/jbc.m110.147801

Abstract

In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75(NTR). During retinal injury, endogenous NGF, TrkA, and p75(NTR) are up-regulated. Paradoxically, neither endogenous NGF nor exogenous administration of wild type NGF can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution of NGF and each of its receptors to RGC degeneration in vivo. During retinal degeneration due to glaucoma or optic nerve transection, treatment with a mutant NGF that only activates TrkA, or with a biological response modifier that prevents endogenous NGF and pro-NGF from binding to p75(NTR) affords significant neuroprotection. Treatment of normal eyes with an NGF mutant-selective p75(NTR) agonist causes progressive RGC death, and in injured eyes it accelerates RGC death. The mechanism of p75(NTR) action during retinal degeneration due to glaucoma is paracrine, by increasing production of neurotoxic proteins TNF-α and α(2)-macroglobulin. Antagonists of p75(NTR) inhibit TNF-α and α(2)-macroglobulin up-regulation during disease, and afford neuroprotection. These data reveal a balance of neuroprotective and neurotoxic mechanisms in normal and diseased retinas, and validate each neurotrophin receptor as a pharmacological target for neuroprotection.

Highlights

Used animal models of neuropathy that cause retinal ganglion cells (RGC) death include ON axotomy and glaucoma
Ocular hypertension is a model of glaucoma that causes chronic and progressive RGC death
ON axotomy is a model of traumatic injury that causes acute and rapid RGC death

Summary

Introduction

Used animal models of neuropathy that cause RGC death include ON axotomy and glaucoma. A second mechanism of RGC death in glaucoma is the increased production of tumor necrosis factor-␣ (TNF-␣) (8 – 10) and ␣2-macroglobulin (␣2M) [11] These neurotoxic factors are produced by activated microglia [12], which express the neurotrophin receptor p75NTR [7]. The retina offers the peculiar advantage that whereas p75 is found almost exclusively on glia/Muller cells, TrkA receptors are almost exclusively expressed in RGCs [7]. This lends to a situation where a ligand such as NGF can bind to each receptor in each cell population, triggering signals that can be beneficial or deleterious. The Duality of Neurotrophin Receptors stand during disease states in which neurotrophic approaches have been attempted to prevent neuronal death

Methods

Results

Conclusion