1. Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism
- Author
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Jose Carlos Rivera, Sang B. Woo, Shi ZhiHua, Marinko V. Sarunic, Alba Galan, Hrishikesh M. Mehta, Jing Xu, H. Uri Saragovi, Kenneth E. Neet, Hinyu Nedev, Yujing Bai, and Pauline Dergham
- Subjects
Retinal degeneration ,genetic structures ,Nerve Tissue Proteins ,Receptors, Nerve Growth Factor ,Pharmacology ,Tropomyosin receptor kinase A ,Biochemistry ,Neuroprotection ,Retinal ganglion ,chemistry.chemical_compound ,Neurobiology ,Nerve Growth Factor ,medicine ,Animals ,Humans ,Receptors, Growth Factor ,alpha-Macroglobulins ,Rats, Wistar ,Receptor, trkA ,Molecular Biology ,Retina ,biology ,Tumor Necrosis Factor-alpha ,Glaucoma ,Neurodegenerative Diseases ,Optic Nerve ,Retinal ,Cell Biology ,Anatomy ,medicine.disease ,eye diseases ,Rats ,Nerve growth factor ,medicine.anatomical_structure ,nervous system ,chemistry ,biology.protein ,Female ,sense organs ,Retinal Neurons ,Neurotrophin - 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.
- Published
- 2010